JP6132321B2 - 改善された脂質製剤 - Google Patents
改善された脂質製剤 Download PDFInfo
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- JP6132321B2 JP6132321B2 JP2015188187A JP2015188187A JP6132321B2 JP 6132321 B2 JP6132321 B2 JP 6132321B2 JP 2015188187 A JP2015188187 A JP 2015188187A JP 2015188187 A JP2015188187 A JP 2015188187A JP 6132321 B2 JP6132321 B2 JP 6132321B2
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Description
本出願は、2009年6月10日に出願された米国特許出願第61/185,800号および2009年9月22日に出願された米国特許出願第61/244,834号に対する優先権を主張し、これらの内容は、その全体が各々参照により本明細書に組み込まれる。
効力を向上するために、研究者らは、化学的に修飾されたまたは修飾されていない治療用核酸を送達するための脂質に基づく担体系も利用している。Zelphati,O and Szoka,F.C.,J.Contr.Rel.41:99−119(1996)において、著者らは、アニオン性(従来の)リポソーム、pH感受性リポソーム、イムノリポソーム、融合性リポソーム、およびカチオン性脂質/アンチセンス凝集体の使用に言及している。同様に、siRNAは、カチオン性リポソーム中で全身投与されており、これらの核酸−脂質粒子は、非ヒト霊長類をはじめとする哺乳動物における標的タンパク質の下方調節を改善することが報告されている(Zimmermann et al.,Nature 441:111−114(2006))。最近の進展にもかかわらず、一般的な治療的使用に好適な改善された脂質−治療用核酸組成物が当該技術分野において依然として必要とされている。これらの組成物は、高効率に核酸を封入し、高い薬物:脂質比を有し、封入された核酸を血清中での分解やクリアランスから保護し、全身送達に好適であり、かつ封入された核酸の細胞内送達をもたらすことが好ましい。さらに、これらの脂質−核酸粒子は、核酸の有効用量での患者治療が患者に対する著しい毒性および/またはリスクを伴わない程度に、十分に忍容性でかつ十分な治療指数を提供すべきである。本発明は、このような組成物、この組成物の作製方法、および疾患治療のためを含む、この組成物を用いた細胞への核酸の導入方法を提供する。
(ターゲッティング基)n−L−脂質
式L
式中、
ターゲッティング基は、当業者に公知のおよび/または本明細書に記載の任意のターゲッティング基(例えば、細胞表面受容体)であり、
nは1〜5の整数(例えば、3)であり、
Lは結合基であり、かつ
脂質は、本明細書に記載の脂質(例えば、DSGなどの中性脂質)などの脂質である。
脂質の比率(単位はモルパーセンテージ)
脂質:siRNA比
50/10/38.5/1.5(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA 約 11
40/15/40/5(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA比 約11
50/10/35/4.5/0.5%(MC3:DSPC:コレステロール:PEG−DSG(C18−PEG):GalNAc3−PEG−DSG)
脂質:siRNA比 約11
50/10/30/9.5/0.5%(MC3:DSPC:コレステロール:PEG−DSG:GalNAc3−PEG−DSG)
脂質:siRNA比 約11
50/10/35/5%(MC3:DSPC:コレステロール:PEG−DSG
脂質:siRNA比 約11
50/10/38.5/1.5(MC3:DPPC:コレステロール:PEG−DMG)
脂質:siRNA 約11
40/15/40/5(MC3:DPPC:コレステロール:PEG−DMG)
脂質:siRNA比 約11
50/10/35/4.5/0.5%(MC3:DPPC:コレステロール:PEG−DSG:GalNAc3−PEG−DSG)
脂質:siRNA比 約11
50/10/30/9.5/0.5%(MC3:DPPC:コレステロール:PEG−DSG:GalNAc3−PEG−DSG)
脂質:siRNA比 約11
50/10/35/5%(MC3:DPPC:コレステロール:PEG−DSG
脂質:siRNA比 約11
50/10/38.5/1.5(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA 約7
50/10/38.5/1.5(MC3:DSPC:コレステロール:PEG−DSG)
脂質:siRNA 約10
50/10/38.5/1.5(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA 約12
50/10/35/5%(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA比 約8
50/10/35/5%(MC3:DSPC:コレステロール:PEG−DMG)
脂質:siRNA比 約10
本明細書で取り上げられる肝臓スクリーニングモデルで試験するための作用剤および/またはアミノ脂質を脂質粒子中に製剤化することができる。脂質粒子としては、リポソームが挙げられるが、これに限定されない。本明細書で使用される場合、リポソームは、水性内部を封入する脂質含有膜を有する構造である。リポソームは1つ以上の脂質膜を有し得る。本発明は、単一膜と呼ばれる単層リポソームと、多重膜と呼ばれる多層リポソームの両方を企図している。核酸と複合体を形成する場合、脂質粒子は、例えば、Feigner,Scientific Americanに記載されているような、DNA層とDNA層の間に挟まれたカチオン性脂質二重層から構成されるリポプレックスでもあり得る。
本発明は、本発明の脂質粒子と活性剤とを含む組成物を含み、その場合、この活性剤は、脂質粒子と関連している。特定の実施形態では、活性剤は治療剤である。特定の実施形態では、活性剤は、脂質粒子の水性内部に封入されている。他の実施形態では、活性剤は、脂質粒子の1つ以上の脂質層の内部に存在する。他の実施形態では、活性剤は、脂質粒子の外部または内部脂質表面に結合している。
特定の実施形態では、本発明の脂質粒子は核酸と関連して、核酸−脂質粒子を生じさせる。特定の実施形態では、核酸は、脂質粒子中に完全に封入されている。本明細書で使用される場合、「核酸」という用語は、任意のオリゴヌクレオチドまたはポリヌクレオチドを含むことが意図されている。最大50個のヌクレオチドを含む断片を通常オリゴヌクレオチドと呼び、それよりも長い断片をポリヌクレオチドと呼ぶ。特定の実施形態では、本発明のオリゴヌクレオチドは20〜50ヌクレオチド長である。
特定の実施形態では、本発明の核酸−脂質粒子は、RNA干渉(RNAi)分子と関連している。RNAi分子を用いたRNA干渉法を用いて、目的の遺伝子またはポリヌクレオチドの発現を妨害し得る。この5年の間に、低分子干渉RNA(siRNA)は、基本的には、開発中の次世代のターゲッティングオリゴヌクレオチド薬物としてアンチセンスODNやリボザイムに取って代わった。siRNAは、RNAi誘導型サイレンシング複合体(RISC)として知られる細胞質の多タンパク質複合体と会合することができる通常21〜30ヌクレオチド長のRNA二重鎖である。siRNAを搭載したRISCは、相同なmRNA転写産物の分解を仲介し、それゆえ、高い特異性をもってタンパク質発現をノックダウンするよう、siRNAを設計することができる。他のアンチセンス技術とは異なり、自然な機構によるsiRNA機能は、非コードRNAを介して遺伝子発現を制御するよう進化した。これは、その活性が、アンチセンスODNまたはリボザイムよりもインビトロおよびインビボで強力である理由であると一般に考えられている。臨床的に意義のある標的を標的とするsiRNAをはじめとする種々のRNAi試薬は現在、例えば、de Fougerolles,A.et al.,Nature Reviews 6:443−453(2007)に記載されているように、医薬品として開発されているところである。
マイクロRNA(miRNA)は、植物および動物のゲノム中のDNAから転写されるが、タンパク質には翻訳されない高度に保存された小RNA分子群である。プロセッシングされたmiRNAは、RNA誘導型サイレンシング複合体(RISC)に取り込まれるようになる約17〜25ヌクレオチド(nt)の一本鎖RNA分子であり、発生、細胞増殖、アポトーシスおよび分化の重要な調節因子として同定されている。これらは、特定のmRNAの3’−非翻訳領域に結合することによって、遺伝子発現の調節に役割を果たしていると考えられている。RISCは、翻訳阻害、転写産物切断、またはその両方によって、遺伝子発現の下方調節を仲介する。RISCは、広範囲にわたる真核生物の核内での転写サイレンシングにも関与する。
一実施形態では、核酸は、標的ポリヌクレオチドに対するアンチセンスオリゴヌクレオチドである。「アンチセンスオリゴヌクレオチド」または単に「アンチセンス」という用語は、ターゲッティングポリヌクレオチド配列に相補的なオリゴヌクレオチドを含むことが意図される。アンチセンスオリゴヌクレオチドは、選ばれた配列に相補的な一本鎖のDNAまたはRNAである。アンチセンスRNAの場合、相補的なRNA鎖に結合することによって、その翻訳を妨げる。アンチセンスDNAは、特異的で、相補的な(コードまたは非コード)RNAを標的するために用いることができる。結合が起こる場合、このDNA/RNAハイブリッドを酵素のRNアーゼHで分解することができる。特定の実施形態では、アンチセンスオリゴヌクレオチドは、約10〜約50ヌクレオチド、より好ましくは約15〜約30ヌクレオチドを含む。この用語は、所望の標的遺伝子と正確には相補的ではない場合があるアンチセンスオリゴヌクレオチドも包含する。したがって、本発明は、非標的特異的活性がアンチセンスで見られる場合に、または標的配列との1つ以上のミスマッチを含むアンチセンス配列が特定の用途で最も好ましい場合に利用することができる。
アンタゴmirは、RNアーゼからの保護ならびに薬理学的特性(例えば、組織および細胞への取込みの増強)のための様々な修飾を有するRNA様オリゴヌクレオチドである。アンタゴmirは、例えば、糖の完全な2’−O−メチル化、ホスホロチオアート骨格、および例えば、3’−末端のコレステロール部分によって、普通のRNAとは異なる。アンタゴmirは、アンタゴmirと内在性miRNAとを含む二重鎖を形成することによって内在性miRNAを効率的にサイレンシングし、それによってmiRNA誘導性の遺伝子サイレンシングを妨害するために使用し得る。アンタゴmir媒介性のmiRNAサイレンシングの例は、Krutzfeldt et al,Nature,2005,438:685−689(これは、その全体が参照により本明細書に明示的に組み込まれる)に記載されている、miR−122のサイレンシングである。アンタゴmir RNAは、標準的な固相オリゴヌクレオチド合成プロトコルを用いて合成し得る。米国特許出願第11/502,158号および同第11/657,341号を参照されたい(これらの内容の開示は、その全体が参照により本明細書に組み込まれる)。
アプタマーは、対象となる特定の分子に高い親和性および特異性で結合する核酸またはペプチド分子である(Tuerk and Gold,Science 249:505(1990);Ellington and Szostak,Nature 346:818(1990))。大きいタンパク質から小さい有機分子まで多くの異なる実体に結合するDNAまたはRNAアプタマーの産生に成功している。Eaton,Curr.Opin.Chem.Biol.1:10−16(1997)、Famulok,Curr.Opin.Struct.Biol.9:324−9(1999)、およびHermann and Patel,Science 287:820−5(2000)を参照されたい。アプタマーは、RNAベースでも、DNAベースでもよく、かつリボスイッチを含んでいてもよい。リボスイッチは、小さい標的分子に直接結合することができ、かつ標的へのその結合が遺伝子の活性に影響を及ぼす、mRNA分子の一部である。したがって、リボスイッチを含むmRNAは、その標的分子の有無によって、それ自体の活性の調節に直接関与する。通常、アプタマーは、小分子、タンパク質、核酸などの様々な分子標的、さらには細胞、組織および生物に結合するように、インビトロ選択を何回も繰り返すことによって、または同等にSELEX(指数関数的濃縮によるリガンドの系統的進化)によって人工的に作製される。アプタマーは、合成法、組換え法、および精製法をはじめとする、任意の既知の方法によって調製されてもよく、単独でまたは同じ標的に特異的な他のアプタマーと組み合わせて使用してもよい。さらに、本明細書でより十分に記載したように、「アプタマー」という用語には、特に、2つ以上の既知のアプタマーと所与の標的との比較から得られるコンセンサス配列を含む「2次アプタマー」が含まれる。
本発明の別の実施形態によれば、核酸−脂質粒子は、リボザイムと会合する。リボザイムは、エンドヌクレアーゼ活性を有する特定の触媒ドメインを有するRNA−タンパク質複合体である(Kim and Cech,Proc Natl Acad Sci USA.1987 Dec;84(24):8788−92;Forster and Symons,Cell.1987 Apr 24;49(2):211−20)。例えば、多数のリボザイムが、しばしばオリゴヌクレオチド基質内のいくつかのリン酸エステルのうちの1つだけを切断する高度の特異性によって、リン酸エステル転移反応を加速させる(Cech et al.,Cell.1981 Dec;27(3 Pt 2):487−96;Michel and Westhof,J Mol Biol.1990 Dec 5;216(3):585−610;Reinhold−Hurek and Shub,Nature.1992 May 14;357(6374):173−6)。この特異性は、基質が化学反応前に特異的な塩基対形成相互作用を介してリボザイムの内部のガイド配列(「IGS」)に結合する必要があることに起因している。
1990年代、DNAベースのアンチセンスオリゴデオキシヌクレオチド(ODN)およびリボザイム(RNA)が、薬物のデザインおよび開発に対して興奮させる新しいパラダイムをもたらしたが、それらのインビボでの適用は、エンド−およびエキソ−ヌクレアーゼ活性ならびに首尾よい細胞内送達の欠如によって妨げられた。この分解の問題は、オリゴヌクレオチド(オリゴ)薬物がヌクレアーゼ酵素によって認識されるのを妨げるが、それらの作用機構を阻害しない化学修飾に対する大規模な研究の後、効果的に克服された。この研究は非常に成功したので、現在開発過程のアンチセンスODN薬物は、未修飾分子の場合の数分間と比較して、インビボで数日間インタクトな状態である(Kurreck,J.2003.Antisense technologies.Improvement through novel chemical modifications.Eur J Biochem 270:1628−44)。しかしながら、細胞内送達および作用機序の問題は、これまで、アンチセンスODNおよびリボザイムが臨床的な製品になることを制限している。
本発明において有用なアンチセンス、siRNAおよび他のオリゴヌクレオチドとしては、修飾された骨格または非天然のヌクレオシド間結合を含むオリゴヌクレオチドが挙げられるが、これに限定されない。修飾された骨格を有するオリゴヌクレオチドには、骨格内にリン原子を保持するオリゴヌクレオチドと骨格内にリン原子を有さないオリゴヌクレオチドが含まれる。ヌクレオシド間骨格内にリン原子を有さない修飾されたオリゴヌクレオチドもまた、オリゴヌクレオシドと考えることができる。修飾されたオリゴヌクレオチド骨格としては、例えば、ホスホロチオアート、キラルホスホロチオアート、ホスホロジチオアート、ホスホトリエステル、アミノアルキルホスホトリ−エステル、メチルホスホナートおよび他のアルキルホスホナート(3’−アルキレンホスホナートおよびキラルホスホナートを含む)、ホスフィナート、ホスホルアミダート(3’−アミノホスホルアミダートおよびアミノアルキルホスホルアミダートを含む)、チオノホスホルアミダート、チオノアルキルホスホナート、チオノアルキルホスホトリエステル、ホスホロセレナート、メチルホスホナートまたはO−アルキルホスホトリエステル結合、ならびに通常の3’−5’結合を有するボラノホスファート、これらの2’−5’結合類似体、および反転した極性を有するもの(ヌクレオシド単位の隣接する対では、3’−5’と5’−3’または2’−5’と5’−2’とが結合する)が挙げられる。本発明による核酸内に存在し得る特定の修飾の特定の非限定的な例を表2に示す。
塩基修飾は、骨格および糖に対する修飾よりも一般的ではない。0.3−6に示す修飾の全てが、ヌクレアーゼに対してsiRNAを安定化させ、活性に対してほとんど効果がないようである(Zhang,H.Y.,Du,Q.,Wahlestedt,C,Liang,Z.2006.RNA Interference with chemically modified siRNA.Curr Top Med Chem 6:893−900)。
糖基におけるほとんどの修飾は、好都合に化学的に反応性の部位を提供する、RNA糖環の2’−OHにおいて生じる。(Manoharan,M.2004.RNA interference and chemically modified small interfering RNAs.Curr Opin Chem Biol 8:570−9;Zhang,H.Y.,Du,Q.,Wahlestedt,C,Liang,Z.2006.RNA Interference with chemically modified siRNA.Curr Top Med Chem 6:893−900)。2’−Fおよび2’−OME(0.7および8)が、一般的であり、その両方が、安定性を高め、2’−OME修飾は、1本の鎖あたり4ヌクレオチド未満に制限される限り、活性を低下させない(Holen,T.,Amarzguioui,M.,Babaie,E.,Prydz,H.2003.Similar behaviour of single−strand and double−strand siRNAs suggests they act through a common RNAi pathway.Nucleic Acids Res 31:2401−7)。修飾塩基がその分子の中央領域に限定されるとき、2’−O−MOE(0.9)は、siRNAにおいて最も有効である(Prakash,T.P.,Allerson,C.R.,Dande,P.,Vickers,T.A.,Sioufi,N.,Jarres,R.,Baker,B.F.,Swayze,E.E.,Griffey,R.H.,Bhat,B.2005.Positional effect of chemical modifications on short interference RNA activity in mammalian cells.J Med Chem 48:4247−53)。活性を失わせることなくsiRNAを安定化させることが見出されている他の修飾を、0.10−14に示す。
所与の化合物における全ての位置が均一に修飾される必要はなく、実際に、上述の修飾のうちの2つ以上が、1つの化合物、またはオリゴヌクレオチド内の1つのヌクレオシドにさえ組み込まれ得る。本発明の特定の好ましいオリゴヌクレオチドは、キメラオリゴヌクレオチドである。「キメラオリゴヌクレオチド」または「キメラ」は、本発明との関連において、各々が少なくとも1つのヌクレオチドで構成されている2つ以上の化学的に異なる領域を含むオリゴヌクレオチドである。これらのオリゴヌクレオチドは、通常、1つ以上の有利な特性(例えば、高いヌクレアーゼ耐性、細胞への高い取り込み、RNA標的に対する高い結合親和性)を付与する修飾ヌクレオチドの少なくとも1つの領域、およびRNaseH切断に対する基質である領域を含む。
本発明の脂質粒子と会合する核酸は、免疫刺激性であってもよく、これには、対象(哺乳動物であっても、または他の患者であってもよい)に投与されたときに、免疫応答を誘導することができる免疫刺激性オリゴヌクレオチド(ISS;一本鎖または二本鎖)が含まれる。ISSには、例えば、ヘアピン二次構造を生じさせる特定のパリンドロム(Yamamoto.,et al.(1992) J.Immunol.148:4072−4076参照)、またはCpGモチーフ、および他の既知のISS特徴(例えば、多重Gドメイン、国際公開第96/11266号参照)が含まれる。
転写因子は、周囲のゲノムDNAがない場合でも、それらの比較的短い結合配列を認識することができるので、特定の転写因子のコンセンサス結合配列を持つ短いオリゴヌクレオチドを、生きた細胞における遺伝子発現を操作するための道具として使用することができる。この戦略では、このような「デコイオリゴヌクレオチド」が細胞内に送達され、その後、標的因子によって認識および結合されることが必要になる。デコイによって転写因子のDNA結合部位が占められると、転写因子が後に標的遺伝子のプロモーター領域に結合することができなくなる。デコイは、転写因子によって活性化される遺伝子の発現を阻害するために、または転写因子の結合によって抑制される遺伝子を上方調節するために、治療剤として使用することができる。デコイオリゴヌクレオチドの利用例は、Mann et al.,J.Clin.Invest.,2000,106:1071−1075に見出すことができ、これは、その全体が参照により本明細書に明示的に組み込まれる。
スーパーmirは、miRNAと実質的に同一であり、かつその標的に対してアンチセンスとなる、ヌクレオチド配列を有する、リボ核酸(RNA)もしくはデオキシリボ核酸(DNA)もしくは両方またはそれらの修飾物の一本鎖、二本鎖または部分的二本鎖オリゴマーまたはポリマーを指す。この用語には、天然に存在するヌクレオ塩基、糖および共有結合的ヌクレオシド間(骨格)結合から構成されるものであって、同様に機能する少なくとも1つの天然には存在しない部分を含む、オリゴヌクレオチドが含まれる。例えば、細胞取込みの増強、核酸標的に対する親和性の増強およびヌクレアーゼ存在下での安定性の増大などの望ましい特性のために、このような修飾または置換オリゴヌクレオチドが天然の形態よりも好ましい。好ましい実施形態では、スーパーmirはセンス鎖を含まず、別の好ましい実施形態では、スーパーmirは、それほど大きく自己ハイブリダイズしない。本発明で取り上げられるスーパーmirは二次構造を有することができるが、生理的条件下では実質的に一本鎖である。実質的に一本鎖のスーパーmirは、スーパーmirの約50%未満(例えば、約40%未満、30%未満、20%未満、10%未満、または5%未満)がそれ自体と二重鎖を形成する程度に一本鎖である。スーパーmirはヘアピン部分を含むことができ、例えば、好ましくは3’末端の配列が自己ハイブリダイズし、二重鎖領域、例えば、少なくとも1、2、3、または4および好ましくは8、7、6、またはnヌクレオチド未満(例えば、5ヌクレオチド)の二重鎖領域を形成することができる。二重鎖を形成した領域は、リンカー、例えば、ヌクレオチドリンカー(例えば、3、4、5、または6つのdT、例えば、修飾dT)によって接続することができる。別の実施形態では、スーパーmirは、例えば、スーパーmirの3’末端と5’末端のうちの一方もしくは両方において、またはスーパーmirの一方の末端と非末端もしくは中央において、例えば、5、6、7、8、9、または10ヌクレオチド長のより短いオリゴと二重鎖を形成する。
miRNA模倣体は、1つ以上のmiRNAの遺伝子サイレンシング能を模倣するために使用することができる一群の分子を表す。したがって、「マイクロRNA模倣体」という用語は、RNAi経路に侵入し、遺伝子発現を調節することができる合成非コードRNAを指す(すなわち、miRNAは、内在性miRNAの源からの精製によって得られない)。miRNA模倣体は、成熟分子(例えば、一本鎖)または模倣体前駆体(例えば、プリ−もしくはプレ−miRNA)として設計することができる。miRNA模倣体は、限定するものではないが、RNA、修飾RNA、DNA、修飾DNA、ロックされた核酸、もしくは2’−O,4’−C−エチレン架橋核酸(ENA)、または上記の任意の組合せ(DNA−RNAハイブリッドを含む)を含むオリゴヌクレオチドを含む核酸(修飾または修飾核酸)から構成され得る。さらに、miRNA模倣体は、送達、細胞内区画化、安定性、特異性、官能性、鎖の用法、および/または効力に影響を及ぼし得るコンジュゲートを含むことができる。ある設計では、miRNA模倣体は、(例えば、約16〜約31ヌクレオチド長の二重鎖領域を有する)二本鎖分子であり、かつ所与のmiRNAの成熟鎖との同一性を有する1つ以上の配列を含む。修飾は、分子の一方または両方の鎖上の2’修飾(2’−Oメチル修飾および2’F修飾を含む)ならびに核酸の安定性および/または特異性を高めるヌクレオチド間修飾(例えば、オスホロチオアート修飾)を含むことができる。さらに、miRNA模倣体は突出を含むことができる。突出は、どちらかの鎖の3’末端または5’末端のどちらかにある1〜6個のヌクレオチドからなることができ、かつ安定性または官能性を高めるように修飾することができる。一実施形態では、miRNA模倣体は、16〜31ヌクレオチドの二重鎖領域と、以下の化学的修飾パターンのうちの1つまたは複数を含む。すなわち、センス鎖は、(センスオリゴヌクレオチドの5’末端から数えて)ヌクレオチド1および2と、CおよびUの全ての、2’−O−メチル修飾を含み、アンチセンス鎖修飾は、CおよびUの全ての2’F修飾と、オリゴヌクレオチドの5’末端のリン酸化と、3’突出の2ヌクレオチドと関連する安定化したヌクレオチド間結合とを含むことができる。
「アンチmir」、「マイクロRNA阻害因子」、「miR阻害因子」、または「阻害因子」という用語は同義的であり、特定のmiRNAの能力に干渉するオリゴヌクレオチドまたは修飾オリゴヌクレオチドを指す。一般に、阻害因子は、本質的に核酸または修飾核酸であり、これには、RNA、修飾RNA、DNA、修飾DNA、ロックされた核酸(LNA)、または上記の任意の組合せを含むオリゴヌクレオチドが含まれる。修飾には、送達、安定性、特異性、細胞内区画化、または効力に影響を及ぼし得る2’修飾(2’−Oアルキル修飾および2’F修飾を含む)ならびにヌクレオチド間修飾(例えば、ホスホロチオアート修飾)が含まれる。さらに、miRNA阻害因子は、送達、細胞内区画化、安定性、および/または効力に影響を及ぼし得るコンジュゲートを含むことができる。阻害因子は、一本鎖、二本鎖(RNA/RNAまたはRNA/DNA二重鎖)、およびヘアピン設計をはじめとする種々の形状を取ることができ、一般に、マイクロRNA阻害因子は、標的とされるmiRNAの成熟鎖(または複数の鎖)と相補的または部分的に相補的な1つ以上の配列または配列の部分を含み、さらに、miRNA阻害因子は、成熟miRNAの逆相補体である配列の5’および3’にある追加の配列も含み得る。追加の配列は、成熟miRNAが由来するプリ−miRNA中の成熟miRNAに隣接する配列の逆相補体であってもよく、または追加の配列は、(A、G、C、またはUの混合物を有する)任意の配列であってもよい。いくつかの実施形態では、追加の配列の一方または両方は、ヘアピンを形成することができる任意の配列である。したがって、いくつかの実施形態では、miRNAの逆相補体である配列は、5’側と3’側にヘアピン構造が隣接している。マイクロRNA阻害因子は、二本鎖を形成したときに、反対鎖のヌクレオチドとの間にミスマッチを含み得る。さらに、マイクロRNA阻害因子を、阻害因子の細胞への取込みを促進するために、コンジュゲート部分に結合させてもよい。例えば、マイクロRNA阻害因子を、マイクロRNA阻害因子の細胞への受動的な取込みを可能にするコレステリル5−(ビス(4−メトキシフェニル)(フェニル)メトキシ)−3ヒドロキシペンチルカルバマート)に結合させてもよい。ヘアピンmiRNA阻害因子をはじめとするマイクロRNA阻害因子は、Vermeulen et al.,“Double−Stranded Regions Are Essential Design Components Of Potent Inhibitors of RISC Function”, RNA 13:723−730(2007)ならびに国際公開第2007/095387号および国際公開第2008/036825号に詳細に記載されており、これらは各々、その全体が参照により本明細書に組み込まれる。当業者は、所望のmiRNAのデータベースから配列を選択し、本明細書に開示されている方法に有用な阻害因子を設計することができる。
U1アダプターはポリA部位を阻害し、標的遺伝子の末端エキソン中の部位に相補的な標的ドメインとU1 snRNPの核内低分子RNA構成要素U1に結合する「U1ドメイン」とを有する二官能性オリゴヌクレオチドである(Goraczniak,et al.,2008,Nature Biotechnology,27(3),257−263、これは、その全体が参照により本明細書に明示的に組み込まれる)。U1 snRNPは、プレ−mRNAエキソン−イントロン境界への結合によってスプライソソーム形成の初期段階を指示するように主に機能するリボヌクレオタンパク質複合体である(Brown and Simpson,1998,Annu Rev Plant Physiol Plant Mol Biol 49:77−95)。U1 snRNA塩基対の5’末端のヌクレオチド2〜11は、プレmRNAの5’ssと結合する。一実施形態では、本発明のオリゴヌクレオチドはU1アダプターである。一実施形態では、U1アダプターは、少なくとも1つの他のiRNA剤と組み合わせて投与することができる。
未修飾のオリゴヌクレオチドは、いくつかの用途では最適とは言えない場合があり、例えば、未修飾のオリゴヌクレオチドが、例えば、細胞ヌクレアーゼによる分解を受けやすい可能性がある。ヌクレアーゼは、核酸のホスホジエステル結合を加水分解することができる。しかしながら、オリゴヌクレオチドの化学修飾は、改善された特性を付与することができ、例えば、ヌクレアーゼに対してオリゴヌクレオチドをより安定にすることができる。
リン酸基は、負に荷電した種である。電荷は、2つの非架橋酸素原子に均等に分布している。しかしながら、リン酸基は、酸素原子の1つを異なる置換基で置換することによって修飾することができる。RNAリン酸骨格に対するこの修飾の1つの結果は、ヌクレアーゼ分解に対するオリゴリボヌクレオチドの耐性の増大であり得る。したがって、理論に束縛されることを望まないが、いくつかの実施形態では、非荷電リンカーかまたは非対称の電荷分布を有する荷電リンカーのいずれかを生じさせる改変を導入することが望ましい可能性がある。
リン酸基は、リン以外のものを含有する接続部に置換することができる。理論によって束縛されることを望まないが、荷電したホスホジエステル基はヌクレアーゼ分解における反応中心なので、これを中性の構造模倣体で置換することは、ヌクレアーゼ安定性を増強するはずであると考えられている。再び、理論によって束縛されることを望まないが、いくつかの実施形態では、荷電したリン酸基が中性部分に置換される改変を導入することが望ましい可能性がある。
リン酸リンカーおよびリボース糖が、ヌクレアーゼ耐性のヌクレオシドまたはヌクレオチドの代用物に置換されているオリゴヌクレオチド模倣スキャフォールドを構築することもできる。理論によって束縛されることを望まないが、繰り返し荷電した骨格が存在しなければ、ポリアニオンを認識するタンパク質(例えば、ヌクレアーゼ)への結合が減少すると考えられている。再び、理論によって束縛されることを望まないが、いくつかの実施形態では、塩基が中性の代用骨格によって連結される改変を導入することが望ましい可能性がある。例としては、モルホリノ、シクロブチル、ピロリジンおよびペプチド核酸(PNA)というヌクレオシド代用物が挙げられる。好ましい代用物はPNA代用物である。
オリゴヌクレオチドの3’末端および5’末端を修飾することができる。このような修飾は、分子の3’末端、5’末端、または両方の末端にあることができる。これらの修飾は、末端リン酸の全体またはリン酸基の原子の1つもしくは複数の修飾または置換を含むことができる。例えば、オリゴヌクレオチドの3’末端および5’末端を、他の機能的分子実体、例えば、標識部分、例えば、フルオロフォア(例えば、ピレン、TAMRA、フルオレセイン、Cy3色素もしくはCy5色素)または保護基(例えば、硫黄、ケイ素、ホウ素もしくはエステルをベースにしたもの)にコンジュゲートすることができる。機能的分子実体は、リン酸基および/またはリンカーを介して糖に付着させることができる。リンカーの末端原子は、リン酸基の結合原子または糖のC−3’もしくはC−5’のO基、N基、S基もしくはC基に接続するかまたはこれらに置き換わることできる。あるいは、リンカーは、ヌクレオチド代用物(例えば、PNA)の末端原子に接続するかまたはこれに置き換わることができる。
アデニン、グアニン、シトシンおよびウラシルはRNAに見られる最も一般的な塩基である。これらの塩基は、改善された特性を有するRNAを提供するために修飾または置換することができる。例えば、ヌクレアーゼ耐性オリゴリボヌクレオチドは、これらの塩基を用いて、または合成もしくは天然のヌクレオ塩基(例えば、イノシン、チミン、キサンチン、ヒポキサンチン、ヌブラリン(nubularine)、イソグアニシン(isoguanisine)、もしくはツベルシジン(tubercidine))および上記の修飾のいずれか1つを用いて調製することができる。あるいは、上記の塩基、例えば、本明細書に記載の「異常塩基」、「修飾塩基」、「非天然塩基」および「汎用塩基」のいずれかの置換類似体または修飾類似体を利用することができる。例としては、限定するものではないが、2−アミノアデニン、アデニンおよびグアニンの6−メチルおよび他のアルキル誘導体、アデニンおよびグアニンの2−プロピルおよび他のアルキル誘導体、5−ハロウラシルおよび5−ハロシトシン、5−プロピニルウラシルおよび5−プロピニルシトシン、6−アゾウラシル、6−アゾシトシンおよび6−アゾチミン、5−ウラシル(シュードウラシル)、4−チオウラシル、5−ハロウラシル、5−(2−アミノプロピル)ウラシル、5−アミノアリルウラシル、8−ハロ、8−アミノ、8−チオール、8−チオアルキル、8−ヒドロキシルおよび他の8−置換アデニンおよびグアニン、5−トリフルオロメチルおよび他の5−置換ウラシルおよびシトシン、7−メチルグアニン、5−置換ピリミジン、6−アザピリミジンならびにN−2置換プリン、N−6置換プリン、およびO−6置換プリン(2−アミノプロピルアデニンを含む)、5−プロピニルウラシルおよび5−プロピニルシトシン、ジヒドロウラシル、3−デアザ−5−アザシトシン、2−アミノプリン、5−アルキルウラシル、7−アルキルグアニン、5−アルキルシトシン、7−デアザアデニン、N6,N6−ジメチルアデニン、2,6−ジアミノプリン、5−アミノ−アリル−ウラシル、N3−メチルウラシル、置換1,2,4−トリアゾール、2−ピリジノン、5−ニトロインドール、3−ニトロピロール、5−メトキシウラシル、ウラシル−5−オキシ酢酸、5−メトキシカルボニルメチルウラシル、5−メチル−2−チオウラシル、5−メトキシカルボニルメチル−2−チオウラシル、5−メチルアミノメチル−2−チオウラシル、3−(3−アミノ−3−カルボキシプロピル)ウラシル、3−メチルシトシン、5−メチルシトシン、N4−アセチルシトシン、2−チオシトシン、N6−メチルアデニン、N6−イソペンチルアデニン、2−メチルチオ−N6−イソペンテニルアデニン、N−メチルグアニン、またはO−アルキル化塩基が挙げられる。さらなるプリンまたはピリミジンとしては、米国特許第3,687,808号に開示されているもの、Concise Encyclopedia Of Polymer Science And Engineering,858−859ページ,Kroschwitz,J.I.,編.John Wiley & Sons,1990に開示されているもの、およびEnglisch et al.,Angewandte Chemie,International Edition,1991,30,613に開示されているものが挙げられる。
オリゴヌクレオチドに対する修飾としては、糖、塩基、および/またはホスファートもしくは修飾リン酸骨格部分のリン原子への1つ以上のカチオン性基の付着を挙げることもできる。カチオン性基を天然の、異常なまたは普遍的な塩基上の置換可能な任意の原子に付着させることができる。好まし位置は、ハイブリダイゼーションを妨げない位置、すなわち、塩基対形成に必要な水素結合相互作用を妨げない位置である。カチオン性基を、例えば、糖のC2’位または環式もしくは非環式糖代用物における類似の位置を介して付着させることができる。カチオン性基としては、例えば、プロトン化アミノ基、例えば、O−アミン(アミン=NH2;アルキルアミノ、ジアルキルアミノ、ヘテロシクリル、アリールアミノ、ジアリールアミノ、ヘテロアリールアミノ、もしくはジヘテロアリールアミノ、エチレンジアミン、ポリアミノ);アミノアルコキシ、例えば、O(CH2)nアミン(例えば、アミン=NH2;アルキルアミノ、ジアルキルアミノ、ヘテロシクリル、アリールアミノ、ジアリールアミノ、ヘテロアリールアミノ、もしくはジヘテロアリールアミノ、エチレンジアミン、ポリアミノ);アミノ(例えば、NH2;アルキルアミノ、ジアルキルアミノ、ヘテロシクリル、アリールアミノ、ジアリールアミノ、ヘテロアリールアミノ、ジヘテロアリールアミノ、もしくはアミノ酸);またはNH(CH2CH2NH)nCH2CH2−アミン(アミン=NH2;アルキルアミノ、ジアルキルアミノ、ヘテロシクリル、アリールアミノ、ジアリールアミノ、ヘテロアリールアミノ、もしくはジヘテロアリールアミノ)に由来するものを挙げることができる。
いくつかの修飾が、特定の場所で、例えば、鎖の内部位置で、またはオリゴヌクレオチドの5’末端もしくは3’末端で、オリゴヌクレオチド上に含まれ得ることが好ましい。オリゴヌクレオチド上の修飾の好ましい場所は薬剤に好ましい特性を付与し得る。例えば、特定の修飾の好ましい場所は、最適な遺伝子サイレンシング特性、またはエンドヌクレアーゼ活性もしくはエキソヌクレアーゼ活性に対する増加した耐性を付与し得る。
本発明に従って使用されるオリゴリボヌクレオチドおよびオリゴリボヌクレオシドは、固相合成を用いて合成されてもよく、例えば、“Oligonucleotide synthesis, a practical approach”,M.J.Gait編,IRL Press,1984;“Oligonucleotides and Analogues, A Practical Approach”,F.Eckstein編,IRL Press,1991(特に、第1章のModern machine−aided methods of oligodeoxyribonucleotide synthesis、第2章のOligoribonucleotide synthesis、第3章の2’−O−Methyloligoribonucleotides:synthesis and applications、第4章のPhosphorothioate oligonucleotides、第5章のSynthesis of oligonucleotide phosphorodithioates、第6章のSynthesis of oligo−2’−deoxyribonucleoside methylphosphonatesおよび第7章のOligodeoxynucleotides containing modified bases)を参照されたい。他の特に有用な合成手順、試薬、ブロッキング基および反応条件は、Martin,P.,Helv.Chim.Acta,1995,78,486−504、Beaucage,S.L.and Iyer,R.P.,Tetrahedron,1992,48,2223−2311およびBeaucage,S.L.and Iyer,R.P.,Tetrahedron,1993,49,6123−6194、またはそれらの中で参照されている参考文献に記載されている。国際公開第00/44895号、国際公開第01/75164号、または国際公開第02/44321号に記載の修飾を本明細書で使用することができる。本明細書に列挙されている全ての刊行物、特許、および公開されている特許出願の開示は、参照により本明細書に組み込まれる。
ホスフィン酸オリゴリボヌクレオチドの調製は、米国特許第5,508,270号に記載されている。アルキルホスホン酸オリゴリボヌクレオチドの調製は、米国特許第4,469,863号に記載されている。ホスホルアミダイトオリゴリボヌクレオチドの調製は、米国特許第5,256,775号または米国特許第5,366,878号に記載されている。ホスホトリエステルオリゴリボヌクレオチドの調製は、米国特許第5,023,243号に記載されている。ボラノリン酸オリゴリボヌクレオチドの調製は、米国特許第5,130,302号および米国特許第5,177,198号に記載されている。3’−デオキシ−3’−アミノホスホルアミダートリボオリゴヌクレオチドの調製は、米国特許第5,476,925号に記載されている。3’−デオキシ3’−メチレンホスホン酸オリゴリボヌクレオチドは、An,H,et al.J.Org.Chem.2001,66,2789−2801に記載されている。硫黄架橋ヌクレオチドの調製は、Sproat et al.Nucleosides Nucleotides 1988,7,651およびCrosstick et al.Tetrahedron Lett.1989,30,4693に記載されている。
2’修飾に対する修飾は、Verma,S.et al.Annu.Rev.Biochem.1998,67,99−134およびその中の全ての参考文献に見出すことができる。リボースに対する特異的修飾は、以下の参考文献に見出すことができる:2’−フルオロ(Kawasaki et.al.,J.Med.Chem.,1993,36,831−841)、2’−MOE(Martin,P.Helv.Chim.Acta 1996,79,1930−1938)、「LNA」(Wengel,J.Acc.Chem.Res.1999,32,301−310)。
メチレンメチルイミノ結合オリゴリボヌクレオシド(本明細書では、MMI結合オリゴリボヌクレオシドとしても識別される)、メチレンジメチルヒドラゾ結合オリゴリボヌクレオシド(本明細書では、MDH結合オリゴリボヌクレオシドとしても識別される)、およびメチレンカルボニルアミノ結合オリゴヌクレオシド(本明細書では、アミド−3結合オリゴリボヌクレオシドとしても識別される)、およびメチレンアミノカルボニル結合オリゴヌクレオシド(本明細書では、アミド−4結合オリゴリボヌクレオシドとしても識別される)、ならびに例えば、MMIとPO結合またはPS結合を交互に有する混合骨格化合物は、米国特許第5,378,825号、同第5,386,023号、同第5,489,677号、ならびに公開されたPCT出願PCT/US92/04294号およびPCT/US92/04305号(それぞれ、国際公開第92/20822号および国際公開第92/20823号として公開されている)に記載されているように調製することができる。ホルムアセタールおよびチオホルムアセタール結合オリゴリボヌクレオシドは、米国特許第5,264,562号および同第5,264,564号に記載されているように調製することができる。エチレンオキシド結合オリゴリボヌクレオシドは、米国特許第5,223,618号に記載されているように調製することができる。シロキサン置換は、Cormier J.F.et al.Nucleic Acids Res.1988,16,4583に記載されている。カルボナート置換は、Tittensor,J.R.J.Chem.Soc.C1971,1933に記載されている。カルボキシメチル置換は、Edge,M.D.et al.J.Chem.Soc.Perkin Trans.1 1972,1991に記載されている。カルバマート置換は、Stirchak,E.P.Nucleic Acids Res.1989,17,6129に記載されている。
シクロブチル糖代用物の化合物は、米国特許第5,359,044号に記載されているように調製することができる。ピロリジン糖代用物は、米国特許第5,519,134号に記載されているように調製することができる。モルホリノ糖代用物は、米国特許第5,142,047号および同第5,235,033号、ならびに他の関連する特許の開示に記載されているように調製することができる。ペプチド核酸(PNA)はそれ自体公知であり、Peptide Nucleic Acids(PNA):Synthesis,Properties and Potential Applications,Bioorganic & Medicinal Chemistry,1996,4,5−23で参照されている様々な手順のいずれかに従って調製することができる。これらはまた、米国特許第5,539,083号に従って調製してもよい。
末端修飾は、Manoharan,M.et al.,Antisense and Nucleic Acid Drug Development 12,103−128(2002)およびその中の参考文献に記載されている。
N−2置換プリンヌクレオシドアミダイトは、米国特許第5,459,255号に記載されているように調製することができる。3−デアザプリンヌクレオシドアミダイトは、米国特許第5,457,191号に記載されているように調製することができる。5,6−置換ピリミジンヌクレオシドアミダイトは、米国特許第5,614,617号に記載されているように調製することができる。5−プロピニルピリミジンヌクレオシドアミダイトは、米国特許第5,484,908号に記載されているように調製することができる。
「リンカー」という用語は、化合物の2つの部分を接続する有機部分を意味する。リンカーとしては、典型的には、直接的な結合、または原子(例えば、酸素もしくは窒素)、単位(例えば、NR1、C(O)、C(O)NH、SO、SO2、SO2NH)または原子鎖(例えば、置換アルキルもしくは未置換アルキル、置換アルケニルもしくは未置換アルケニル、置換アルキニルもしくは未置換アルキニル、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアリールアルキル、ヘテロアリールアルケニル、ヘテロアリールアルキニル、ヘテロシクリルアルキル、ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、アリール、ヘテロアリール、ヘテロシクリル、シクロアルキル、シクロアルケニル、アルキルアリールアルキル、アルキルアリールアルケニル、アルキルアリールアルキニル、アルケニルアリールアルキル、アルケニルアリールアルケニル、アルケニルアリールアルキニル、アルキニルアリールアルキル、アルキニルアリールアルケニル、アルキニルアリールアルキニル、アルキルヘテロアリールアルキル、アルキルヘテロアリールアルケニル、アルキルヘテロアリールアルキニル、アルケニルヘテロアリールアルキル、アルケニルヘテロアリールアルケニル、アルケニルヘテロアリールアルキニル、アルキニルヘテロアリールアルキル、アルキニルヘテロアリールアルケニル、アルキニルヘテロアリールアルキニル、アルキルヘテロシクリルアルキル、アルキルヘテロシクリルアルケニル、アルキルヘテロシクリルアルキニル、アルケニルヘテロシクリルアルキル、アルケニルヘテロシクリルアルケニル、アルケニルヘテロシクリルアルキニル、アルキニルヘテロシクリルアルキル、アルキニルヘテロシクリルアルケニル、アルキニルヘテロシクリルアルキニル、アルキルアリール、アルケニルアリール、アルキニルアリール、アルキルヘテロアリール、アルケニルヘテロアリール、アルキニルヘテロアリール(ここで、1つ以上のメチレンは、O、S、S(O)、SO2、N(R1)2、C(O)、切断可能な結合基、置換アリールもしくは未置換アリール、置換ヘテロアリールもしくは未置換ヘテロアリール、置換複素環もしくは未置換複素環によって中断もしくは終結されることがあり;R1は、水素、アシル、脂肪族もしくは置換脂肪族である))が挙げられる。
式中、
P、R、T、P’、R’およびTは、各出現について各々独立に、存在しないか、CO、NH、O、S、OC(O)、NHC(O)、CH2、CH2NH、CH2O;NHCH(Ra)C(O)、−C(O)−CH(Ra)−、NH−、CH=N−O、
QおよびQ’は、各出現について各々独立に、存在しないか、−(CH2)n−、−C(R1)(R2)(CH2)n−、−(CH2)nC(R1)(R2)−、−(CH2CH2O)mCH2CH2−、または−(CH2CH2O)mCH2CH2NH−であり、
Xは存在しないかまたは切断可能な結合基であり、
RaはHまたはアミノ酸側鎖であり、
R1およびR2は、各出現について各々独立に、H、CH3、OH、SHまたはN(RN)2であり、
RNは、各出現について独立に、H、メチル、エチル、プロピル、イソプロピル、ブチルまたはベンジルであり、
q、q’およびq”は、各出現について各々独立に、0〜20であり、ここで、繰返し単位は同じものまたは異なるものであることができ、
nは、各出現について独立に、0〜20であり、かつ
mは、各出現について独立に、0〜50である。
切断可能な結合基とは、細胞外では十分に安定であるが、標的細胞内に入ると切断され、リンカーが結び付けている2つの部分を放出する基のことである。好ましい実施形態では、切断可能な結合基は、対象の血液中、または第2の参照条件(例えば、血液中もしくは血清中に見られる条件を模倣するかもしくはそのような条件に相当するように選択することができる)下よりも少なくとも10倍以上、好ましくは少なくとも100倍以上速く、標的細胞内または第1の参照条件(例えば、細胞内条件を模倣かもしくはそのような条件に相当するように選択することができる)下で分解される。
切断可能な結合基の1つの部類は、還元または酸化によって切断されるレドックス切断可能な結合基である。還元切断可能な結合基の例は、ジスルフィド結合基(−S−S−)である。候補となる切断可能な結合基が、好適で「還元切断可能な結合基」であるかどうか、または例えば、特定のiRNA部分および特定のターゲッティング剤とともに使用するのに好適であるかどうかを明らかにするために、本明細書に記載の方法に目を向けることができる。例えば、候補は、ジチオスレイトール(DTT)、または細胞(例えば、標的細胞)で観察される切断の速度を模倣する、当該技術分野で公知の試薬を用いる他の還元剤とともにインキュベートすることによって評価することができる。候補は、血液条件または血清条件を模倣するように選択される条件下で評価することもできる。好ましい実施形態では、候補化合物は、血液中で多くても10%切断される。好ましい実施形態では、有用な候補化合物は、血液(または細胞外条件を模倣するように選択されたインビトロ条件下)と比較したとき、少なくとも2倍、4倍、10倍または100倍速く、細胞内で(または細胞内条件を模倣するように選択されたインビトロ条件下)分解される。候補化合物の切断の速度を、細胞内媒体を模倣するように選択された条件下で、標準的な酵素動力学アッセイを用いて測定し、細胞外媒体を模倣するように選択された条件と比較することができる。
リン酸ベースの切断可能な結合基は、リン酸基を分解または加水分解する薬剤によって切断される。細胞内のリン酸基を切断する薬剤の例は、細胞内のホスファターゼなどの酵素である。リン酸ベースの結合基の例は、−O−P(O)(ORk)−O−、−O−P(S)(ORk)−O−、−O−P(S)(SRk)−O−、−S−P(O)(ORk)−O−、−O−P(O)(ORk)−S−、−S−P(O)(ORk)−S−、−O−P(S)(ORk)−S−、−S−P(S)(ORk)−O−、−O−P(O)(Rk)−O−、−O−P(S)(Rk)−O−、−S−P(O)(Rk)−O−、−S−P(S)(Rk)−O−、−S−P(O)(Rk)−S−、−O−P(S)(Rk)−S−である。好ましい実施形態は、−O−P(O)(OH)−O−、−O−P(S)(OH)−O−、−O−P(S)(SH)−O−、−S−P(O)(OH)−O−、−O−P(O)(OH)−S−、−S−P(O)(OH)−S−、−O−P(S)(OH)−S−、−S−P(S)(OH)−O−、−O−P(O)(H)−O−、−O−P(S)(H)−O−、−S−P(O)(H)−O−、−S−P(S)(H)−O−、−S−P(O)(H)−S−、−O−P(S)(H)−S−である。好ましい実施形態は、−O−P(O)(OH)−O−である。これらの候補は、上記の方法と類似の方法を用いて評価することができる。
酸切断可能な結合基とは、酸性条件下で切断される結合基のことである。好ましい実施形態では、酸切断可能な結合基は、pH約6.5以下(例えば、約6.0、5.5、5.0、もしくはそれ未満)の酸性環境において、または一般酸として作用することができる酵素などの薬剤によって切断される。細胞において、特定の低pHのオルガネラ(例えば、エンドソームおよびリソソーム)は、酸切断可能な結合基に対する切断環境を提供することができる。酸切断可能な結合基の例としては、ヒドラゾン、エステル、およびアミノ酸のエステルが挙げられるが、これらに限定されない。酸切断可能な基は、一般式−C=NN−、C(O)O、または−OC(O)を有することができる。好ましい実施形態は、エステル(アルコキシ基)の酸素に結合した炭素が、アリール基、置換アルキル基、または三級アルキル基(例えば、ジメチル、ペンチルもしくはt−ブチル)である場合である。これらの候補は、上記の方法と類似の方法を用いて評価することができる。
エステルベースの切断可能な結合基は、細胞内のエステラーゼおよびアミダーゼなどの酵素によって切断される。エステルベースの切断可能な結合基の例としては、アルキレン基、アルケニルレン基およびアルキニレン基のエステルが挙げられるが、これらに限定されない。エステル切断可能な結合基は、一般式−C(O)O−または−OC(O)−を有する。これらの候補は、上記の方法と類似の方法を用いて評価することができる。
ペプチドベースの切断可能な結合基は、細胞内のペプチダーゼおよびプロテアーゼなどの酵素によって切断される。ペプチドベースの切断可能な結合基とは、アミノ酸とアミノ酸の間で形成されて、オリゴペプチド(例えば、ジペプチド、トリペプチドなど)およびポリペプチドを生じさせるペプチド結合のことである。ペプチドベースの切断可能基には、アミド基(−C(O)NH−)は含まれない。アミド基は、任意のアルキレン、アルケニレンまたはアルキニレンの間で形成させることができる。ペプチド結合は、アミノ酸とアミノ酸の間で形成されて、ペプチドおよびタンパク質を生じさせる特殊なタイプのアミド結合である。ペプチドベースの切断可能基は、通常、アミノ酸とアミノ酸の間で形成されて、ペプチドおよびタンパク質を生じさせるペプチド結合(すなわち、アミド結合)に限定され、アミド官能基全体を含むものではない。ペプチドベースの切断可能な結合基は、一般式−NHCHRAC(O)NHCHRBC(O)−(式中、RAとRBは、2つの隣接するアミノ酸のR基である)を有する。これらの候補は、上記の方法と類似の方法を用いて評価することができる。
多種多様な実体を本発明のオリゴヌクレオチドおよび脂質に結合させることができる。好ましい部分は、介在テザーを介して直接的にかまたは間接的にかのいずれかで、好ましくは共有結合によって結合されるリガンドである。
参考文献
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2.Vogel et al.,J.Am.Chem.Soc.,1996,118:1581−1586.
3.Turk,M.J.,Reddy,J.A et al.(2002).Characterization of a novel pH−sensitive peptide that enhances drug release from folate−targeted liposomes at endosomal pHs.Biochim.Biophys.Acta 1559,56−68.
4.Plank,C.Oberhauser,B.Mechtler,K.Koch,C.Wagner,E.(1994).The influence of endosome−disruptive peptides on gene transfer using synthetic virus−like gene transfer systems,J.Biol.Chem.269 12918−12924.
5.Mastrobattista,E.,Koning,G.A.et al.(2002).Functional characterization of an endosome−disruptive peptide and its application in cytosolic delivery of immunoliposome−entrapped proteins.J.Biol.Chem.277,27135−43.
6.Oberhauser,B.,Plank,C.et al.(1995).Enhancing endosomal exit of nucleic acids using pH−sensitive viral fusion peptides.Deliv.Strategies Antisense Oligonucleotide Ther.247−66.
便宜のため、本明細書、実施例、および付随する特許請求の範囲で使用される特定の用語および語句の意味が、以下に提供される。本明細書の他の部分におけるある用語の用法と本節で示されるその定義との間に明白な矛盾がある場合には、本節の定義が優先されるものとする。
特定の実施形態では、本発明は、脂質に封入された核酸粒子を生成するための方法および組成物に関し、この粒子中で、核酸は脂質層内に封入される。siRNAオリゴヌクレオチドを組み込んでいるこのような核酸−脂質粒子は:(1)薬物対脂質比;(2)封入効率;および(3)粒径をはじめとする種々の生物物理学的パラメータを用いて特徴付けられる。高い薬物対脂質比、高い封入効率、良好なヌクレアーゼ耐性および血清安定性、ならびに調節可能な粒径(通常、直径200nm未満)が望ましい。さらに、ヌクレアーゼ耐性を付与するための核酸の修飾が、治療薬のコストに加えられるが、多くの場合、限られた耐性しか提供しないので、核酸ポリマーの性質が重要である。特に記述されない限り、これらの基準は、本明細書中で以下の通りに計算される。
本発明の方法および組成物は、特定のカチオン性脂質を利用し、その脂質の合成、調製および特徴づけは、以下および添付の実施例において説明される。さらに、本発明は、治療剤(例えば、核酸)と会合した脂質粒子をはじめとする脂質粒子を調製する方法を提供する。本明細書で記載される方法において、脂質の混合物は、核酸の緩衝水溶液と組み合わされて、脂質粒子内に封入された核酸を含む中間体混合物を生成し、その場合、この封入された核酸は、約3重量%〜約25重量%、好ましくは5〜15重量%という核酸/脂質比で存在する。この中間体混合物は、脂質に封入された核酸粒子を得るために、場合によって大きさが揃えられてもよく、その場合、この脂質部分は、好ましくは30〜150nmの直径、より好ましくは約40〜90nmの直径を有する単層小胞である。次に、pHを上げて、脂質−核酸粒子上の表面電荷の少なくとも一部を中和し、それにより、少なくとも部分的に表面が中和された、脂質に封入された核酸組成物が提供される。
本発明の脂質粒子は、インビトロまたはインビボで治療剤を細胞に送達するために使用され得る。特定の実施形態では、治療剤は、本発明の核酸−脂質粒子を用いて細胞に送達される核酸である。本発明の脂質粒子および関連する薬学的組成物を使用する様々な方法の以下の説明は、核酸−脂質粒子に関する説明によって例証されるが、これらの方法および組成物が、そのような治療の恩恵を受ける任意の疾患または障害を治療するための任意の治療剤を送達するために容易に適応され得ることが理解される。
一実施形態では、本発明は、本明細書に記載の肝臓スクリーニングモデルで同定された核酸剤を含む薬学的組成物を提供する。組成物は、作用剤(例えば、dsRNA)と薬学的に許容される担体とを含む。薬学的組成物は、遺伝子の発現または活性と関連する疾患または障害を治療するのに有用である。このような薬学的組成物は、送達の様式に基づいて製剤化される。1つの例は、非経口送達を介する全身投与用に製剤化される組成物である。
インビボでの齧歯類第VII因子およびApoBのサイレンシング実験。C57BL/6マウス(Charles River Labs,MA)とSprague−Dawleyラット(Charles River Labs,MA)に、尾静脈注射によって、0.01mL/gの容量で、食塩水または所望の製剤中のsiRNAのいずれかを投与した。投与後の様々な時点で、動物にイソフルオラン吸入で麻酔をかけ、血液を後眼窩採血によって血清分離チューブ中に回収した。第VII因子タンパク質の血清レベルを、製造元のプロトコルに従って発色アッセイ(Coaset Factor VII,DiaPharma Group,OHまたはBiophen FVII,Aniara Corporation,OH)を用いて試料中で決定した。食塩水処理した動物から回収した血清を用いて標準曲線を作成した。投与後の様々な時点で、肝臓mRNAレベルを評価する実験において、動物を屠殺し、肝臓を摘出し、液体窒素中で瞬間凍結した。凍結した肝臓組織をすり潰して粉末にした。組織ライセートを調製し、第VII因子およびapoBの肝臓mRNAレベルを、分岐DNAアッセイ(QuantiGene Assay,Panomics,CA)を用いて決定した。
凝固カスケードの著名なタンパク質である第VII因子(FVII)は、肝臓(肝細胞)で合成され、血漿中に分泌される。血漿中のFVIIレベルは、簡単なプレートに基づく比色アッセイで決定することができる。したがって、FVIIは、siRNA媒介性の肝細胞由来タンパク質の下方調節の決定、ならびに核酸脂質粒子およびsiRNAの血漿濃度および組織分布のモニタリングのための好都合なモデルである。
C57BL/6マウスで静脈内(ボーラス)注射した24時間後、FVII活性をFVII siRNA処理動物で評価した。マイクロプレートスケールで、製造元の指示に従って、血清または組織中のタンパク質レベルを決定するための市販キットを用いてFVIIを測定した。FVIIの低下を未処理の対照マウスに対して決定し、結果を残存FVII%として表した。4つの用量レベル(2、5、12.5、25mg/kg FVII siRNA)を各々の新規リポソーム組成物の初期スクリーンで用い、初期スクリーンで得られた結果を基にして、この用量を後の研究で拡大した。
体重変化、臨床観察、臨床化学検査および、場合によって、血液検査をモニタリングすることにより、各々の新規リポソームsiRNA製剤の認容性を評価した。処理前および処理24時間後に、動物の体重を記録した。データを体重変化%として記録した。体重測定に加えて、肝機能マーカーを含む、完全な臨床化学検査パネルを、FVII解析用に採取された血清のアリコートを用いて、注射24時間後に、各用量レベル(2、5、12.5および25mg/kg siRNA)で得た。解析のために、試料をCentral Laboratory for Veterinarians(Langley,BC)に送付した。場合によっては、血液検査解析用の全血の採取が行えるように、治療群に追加のマウスを含めた。
治療指数(TI)は、毒性と活性の測定値を比較して生成される任意のパラメータである。これらの研究のために、TIを
TI=MTD(最大忍容用量)/ED50(50%のFVIIノックダウンが得られる用量)
として計算する。
1,2−ジ−O−テトラデシル−sn−グリセリドIa(30g、61.80mmol)およびN,N’−スクシンイミジルカルボナート(DSC、23.76g、1.5当量)をジクロロメタン(DCM、500mL)中に入れ、氷水混合物上で撹拌した。この撹拌溶液中にトリエチルアミン(TEA、25.30mL、3当量)を添加し、その後、反応混合物を周囲温度で一晩撹拌させておいた。反応の進行をTLCでモニタリングした。反応混合物をDCM(400mL)で希釈し、有機層を水(2×500mL)、NaHCO3(500mL)水溶液で洗浄した後、標準的な後処理をした。得られた残渣を高真空下にて周囲温度で一晩乾燥させた。乾燥後、このようにして得られた粗カルボナートIIaをジクロロメタン(500mL)に溶解させ、氷浴上で撹拌した。この撹拌溶液に、mPEG2000−NH2(III、103.00g、47.20mmol、NOF Corporation,Japanから購入)および無水ピリジン(Py、80mL、過剰)をアルゴン下で添加した。次に、反応混合物を周囲温度で一晩撹拌させておいた。溶媒および揮発性物質を真空下で除去し、残渣をDCM(200mL)に溶解させ、酢酸エチル中に詰めたシリカゲルカラムに充填した。カラムを最初に酢酸エチル、その後ジクロロメタン中の5〜10%メタノール勾配で溶出させると、所望のPEG−脂質IVaが白色の固体(105.30g、83%)として得られた。1H NMR(CDCl3,400MHz) δ=5.20−5.12(m,1H),4.18−4.01(m,2H),3.80−3.70(m,2H),3.70−3.20(m,−O−CH2−CH2−O−,PEG−CH2),2.10−2.01(m,2H),1.70−1.60(m,2H),1.56−1.45(m,4H),1.31−1.15(m,48H),0.84(t,J=6.5Hz,6H)。MS範囲実測値:2660−2836。
1,2−ジ−O−ヘキサデシル−sn−グリセリドIb(1.00g、1.848mmol)およびDSC(0.710g、1.5当量)を一緒にジクロロメタン(20mL)中に入れ、氷水混合物中で0℃に冷却した。トリエチルアミン(1.00mL、3当量)を添加し、反応液を一晩撹拌した。反応後、TLCにかけ、DCMで希釈し、水(2回)、NaHCO3溶液で洗浄し、硫酸ナトリウム上で乾燥させた。溶媒を減圧下で除去し、得られたIIbの残渣を高真空下で一晩維持した。この化合物をさらに精製することなく次の反応に直接用いた。MPEG2000−NH2 III(1.50g、0.687mmol、NOF Corporation,Japanから購入)およびIIb(0.702g、1.5当量)をアルゴン下でジクロロメタン(20mL)に溶解させた。反応液を0℃に冷却した。ピリジン(1mL、過剰)を添加し、反応液を一晩撹拌した。反応をTLCでモニタリングした。溶媒および揮発性物質を真空下で除去し、残渣をクロマトグラフィー(最初に酢酸エチル、次いで勾配溶出としての5〜10%MeOH/DCM)で精製すると、所要の化合物IVbが白色の固体(1.46g、76%)として得られた。1H NMR(CDCl3,400MHz) δ=5.17(t,J=5.5Hz,1H),4.13(dd,J=4.00Hz,11.00Hz,1H),4.05(dd,J=5.00Hz,11.00Hz,1H),3.82−3.75(m,2H),3.70−3.20(m,−O−CH2−CH2−O−,PEG−CH2),2.05−1.90(m,2H),1.80−1.70(m,2H),1.61−1.45(m,6H),1.35−1.17(m,56H),0.85(t,J=6.5Hz,6H)。MS範囲実測値:2716−2892。
1,2−ジ−O−オクタデシル−sn−グリセリドIc(4.00g、6.70mmol)およびDSC(2.58g、1.5当量)を一緒にジクロロメタン(60mL)中に入れ、氷水混合物中で0℃に冷却した。トリエチルアミン(2.75mL、3当量)を添加し、反応液を一晩撹拌した。反応後、TLCにかけ、DCMで希釈し、水(2回)、NaHCO3溶液で洗浄し、硫酸ナトリウム上で乾燥させた。溶媒を減圧下で除去し、残渣を高真空下で一晩維持した。この化合物をさらに精製することなく次の反応に直接用いた。MPEG2000NH2 III(1.50g、0.687mmol、NOF Corporation,Japanから購入)およびIIc(0.760g、1.5当量)をアルゴン下でジクロロメタン(20mL)に溶解させた。反応液を0℃に冷却した。ピリジン(1mL、過剰)を添加し、反応液を一晩撹拌した。反応をTLCでモニタリングした。溶媒および揮発性物質を真空下で除去し、残渣をクロマトグラフィー(酢酸エチル、次いで勾配溶出としての5〜10%MeOH/DCM)で精製すると、所望の化合物IVcが白色の固体(0.92g、48%)として得られた。1H NMR(CDCl3,400MHz) δ=5.22−5.15(m,1H),4.16(dd,J=4.00Hz,11.00Hz,1H),4.06(dd,J=5.00Hz,11.00Hz,1H),3.81−3.75(m,2H),3.70−3.20(m,−O−CH2−CH2−O−,PEG−CH2),1.80−1.70(m,2H),1.60−1.48(m,4H),1.31−1.15(m,64H),0.85(t,J=6.5Hz,6H)。MS範囲実測値:2774−2948。
(6Z,9Z,28Z,31Z)−ヘプタトリアコンタ−6,9,28,31−テトラエン−19−オール(0.53g)、4−N,N−ジメチルアミノ酪酸塩酸塩(0.51g)、4−N,N−ジメチルアミノピリジン(0.61g)および1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(0.53g)のジクロロメタン(5mL)溶液を室温で一晩撹拌した。この溶液を希塩酸、次いで希釈重炭酸ナトリウム水溶液で洗浄した。有機画分を無水硫酸マグネシウム上で乾燥させ、濾過し、溶媒をロータリーエバポレーター(ロトバップ)で除去した。残渣を、1〜5%メタノール/ジクロロメタン溶出勾配を用いて、シリカゲルカラム(20g)に通した。精製物を含む画分を組合せ、溶媒を除去すると、無色のオイル(0.54g)が得られた。
1.Schlueter,Urs;Lu,Jun;Fraser−Reid,Bert.Synthetic Approaches To Heavily Lipidated Phosphoglyceroinositides.Organic Letters(2003),5(3),255−257.
2.King,J.F.;Allbutt,A.D.Can.J.Chem.1970,48,1754−1769
3.Mach,Mateusz;Schlueter,Urs;Mathew,Felix;Fraser−Reid,Bert;Hazen,Kevin C.Comparing n−pentenyl orthoesters and n−pentenyl glycosides as alternative glycosyl donors.Tetrahedron(2002),58(36),7345−7354.
ラットにおけるMC3含有リポソーム製剤の用量応答を調べるために、以下のリポソーム製剤を本質的に実施例2に記載した通りに調製した。下記の表に示すように、含まれる成分を次の通りに示す:MC3−DSPC−コレステロール−PEG−C14。下記の表9に、試験した例示的な製剤を示す。
様々なリポソーム製剤の効力におけるApoEの役割をさらに調べるために、野生型マウスおよびApoEノックアウトマウスに、0.1、0.03、および0.01mg/kgのAD−1661 siRNA組成物を含むMC3リポソームを本質的に実施例2に記載した通りに投与した。ApoEを外から添加することで、マウスにおけるタンパク質の欠如を克服することができるかどうかを明らかにするために、リポソーム製剤の半分を組換えApoEタンパク質と事前混合した。下記の表10に、試験した例示的な製剤を示す。
モルパーセンテージおよびホスホコリンのテールの長さの変化が様々なリポソーム製剤の効力に及ぼす効果を調べるために、DSPC、DMPCおよびDLPCを含む様々な製剤を0.01または0.03mg/kgでFVIIサイレンシングの効力について試験した。
潜在的な代替送達機構を探索するために、N−アセチルガラクトサミン(GalNAc)コンジュゲート脂質を含むリポソーム製剤を用いてインビボ実験を行なった。GalNAcをターゲッティングリガンド候補として選んだが、それは、GalNAc受容体が肝臓で高度に発現されると考えられることが知られているからである。それゆえ、マウスおよびラットで研究を行ない、式IIIのGalNAc3−PEG−DSG脂質をさらに含むMC3含有リポソーム製剤の効力を本質的に実施例2に記載した通りに試験した。全ての実験において、PEGコンジュゲート脂質の総量を一定に保った(例えば、0.5%molのGalNAc3−PEGを添加する場合、対応するPEG−DSGの量を0.5%molだけ減らした)。実験では遺伝子型ごとの9つの群の各々について4匹の動物を用いた。
GalNAc3−PEG−DSGを含むおよび含まない、様々なモルパーセンテージの成分を有するMC3含有リポソームの効力を明らかにするために、以下のリポソーム製剤を、実質的に上記の実施例2に記載した通りに調製し、C57BL6マウスで試験した。表に記載された成分は、次のような順で示されている:MC3/DSPC/Chol/PEG−DSG。0.5%のGalNAc3−PEGを添加する場合、下記の表16に示すように、対応するPEG−DSGの量を4.5%に低下させる。
様々なリポソーム製剤の効力におけるASGPRの役割を調べるために、野生型マウスおよびASGPRノックアウトマウスに、実施例1に記載したような3、1、および0.3mg/kgのAD−1661 siRNA組成物を含有するMC3リポソームを投与した。表に記載された成分は、次のような順で示されている:MC3/DSPC/Chol/PEG−DSG。0.5%のGalNAc3−PEGを添加する場合、下記の表17に示すように、対応するPEG−DSGの量を9.5%に低下させる。
合成
オリゴヌクレオチドは全て、AKTAオリゴパイロット合成装置で合成する。市販の多孔質ガラス(controlled pore glass)固体支持体(dT−CPG、500A、Prime Synthesis)および標準的な保護基を有するRNAホスホルアミダイトである、5’−O−ジメトキシトリチルN6−ベンゾイル−2’−t−ブチルジメチルシリル−アデノシン−3’−O−N,N’−ジイソプロピル−2−シアノエチルホスホルアミダイト、5’−O−ジメトキシトリチル−N4−アセチル−2’−t−ブチルジメチルシリル−シチジン−3’−O−N,N’−ジイソプロピル−2−シアノエチルホスホルアミダイト、5’−O−ジメトキシトリチル−N2−イソブトリル−2’−t−ブチルジメチルシリル−グアノシン−3’−O−N,N’−ジイソプロピル−2−シアノエチルホスホルアミダイト、および5’−O−ジメトキシトリチル−2’−t−ブチルジメチルシリル−ウリジン−3’−O−N,N’−ジイソプロピル−2−シアノエチルホスホルアミダイト(Pierce Nucleic Acids Technologies)をオリゴヌクレオチド合成に用いた。2’−Fホスホルアミダイト、5’−O−ジメトキシトリチル−N4−アセチル−2’−フルロ−シチジン−3’−O−N,N’−ジイソプロピル−2−シアノエチル−ホスホルアミダイトおよび5’−O−ジメトキシトリチル−2’−フルロ−ウリジン−3’−O−N,N’−ジイソプロピル−2−シアノエチル−ホスホルアミダイトは(Promega)から購入する。
合成が終了した後、支持体を100mLガラスボトル(VWR)に移す。オリゴヌクレオチドを支持体から切り離し、塩基とリン酸基を80mLのエタノールアンモニア混合物[アンモニア:エタノール(3:1)]を用いて55℃で6.5時間同時に脱保護する。ボトルを氷上で短時間冷却した後、エタノールアンモニア混合物を濾過して、新しい250−mLボトルに入れる。CPGを2×40mL部のエタノール/水(1:1 v/v)で洗浄する。次に、混合物の容量をロータリーエバポレーター(ロトバップ)で約30mLにまで減らす。次に、混合物をドライアイス上で凍結させ、スピードバックにて真空下で乾燥させる。
乾燥残渣を、トリエチルアミンとトリエチルアミントリヒドロフルオリド(TEA・3HF)またはピリジン−HFとDMSO(3:4:6)26mLに再懸濁し、60℃で90分間加熱して、2’位のtert−ブチルジメチルシリル(TBDMS)基を除去する。次に、反応液を50mLの20mM酢酸ナトリウムでクエンチし、そのpHを6.5に調整する。オリゴヌクレオチドを精製するまでフリーザーで保存する。
オリゴヌクレオチドは高速液体クロマトグラフィー(HPLC)で分析された後に精製され、緩衝液およびカラムの選択は、配列および/またはコンジュゲートされたリガンドの性質によって決まる。
リガンドがコンジュゲートされたオリゴヌクレオチドを逆相分取HPLCで精製する。コンジュゲートしていないオリゴヌクレオチドを自前で詰めたTSKゲルカラム上での陰イオン交換HPLCで精製する。緩衝液は、10%CH3CN(緩衝液A)中の20mMリン酸ナトリウム(pH8.5)および10%CH3CN、1M NaBr(緩衝液B)中の20mMリン酸ナトリウム(pH8.5)である。全長オリゴヌクレオチドを含む画分をプールし、脱塩し、凍結乾燥させる。OD約0.15の脱塩オリゴヌクレオチドを150μLになるまで水に希釈した後、CGEおよびLC/MS分析用の特別なバイアルにピペッティングで入れる。次に、化合物をLC−ESMSおよびCGEで分析する。
PEG−脂質(例えば、mPEG2000−1,2−ジ−O−アルキル−sn3−カルボモイルグリセリド)を以下の手順を用いて合成した。
脂質(式Iのカチオン性脂質、DSPC、コレステロール、DMG−PEG)を可溶化し、所望のモル比に従ってエタノール中で混合する。混合した脂質をpH5.2の酢酸ナトリウム緩衝液に添加するエタノール注入法によって、リポソームを形成させる。これにより、35%エタノール中でリポソームが自然に形成される。リポソームを0.08μmポリカーボネート膜に少なくとも2回通して押し出す。ストックsiRNA溶液を酢酸ナトリウムおよび35%エタノール中に調製し、リポソームに添加して、充填(load)した。siRNA−リポソーム溶液を37℃で30分間インキュベートし、その後、希釈した。エタノールを除去し、透析または接線流濾過でPBS緩衝液に交換した。
一方は脂質を含み、もう一方はsiRNAを含む、個々別々のストックを調製する。式Iのカチオン性脂質、DSPC、コレステロールおよびPEG脂質を含む脂質ストックを90%エタノールに可溶化して調製する。残りの10%は低pHクエン酸緩衝液である。脂質ストックの濃度は4mg/mLである。このクエン酸緩衝液のpHの範囲は、利用される融合性脂質の種類によって、pH3〜5であることができる。siRNAを4mg/mLの濃度でクエン酸緩衝液にも可溶化する。小規模用に、5mLの各ストック溶液を調製する。
アルゴン注入口とサーモウェルとが取り付けられたきれいな乾燥した200Lのガラス反応器に60LのTHFと5.73Kg(20.4mol)のリノール酸とを充填した。反応器の内容物をアセトン−ドライアイス浴を用いて0℃未満に冷却した。この冷たい溶液に、トルエン中の13.8Lのビトライド(60%重量/体積)をゆっくりと添加し、反応混合物の内部温度を0℃未満に維持した(注:最初のビトライドの添加は発熱性であり、発泡が観察された。添加してから15分後に発泡は止まった)。ビトライドの添加には3時間45分かかった。添加し終わった後、反応混合物を周囲温度で2時間撹拌した。アリコートを取り、飽和Na2SO4でクエンチし、このようにして得られた粗生成物を出発酸の存在についてTLCで分析した。TLCは反応の完了を示しており、この反応混合物を約45分間で再び0℃未満に冷却した。この混合物に(1.1Kgの硫酸ナトリウムを1.5Lの水に溶解させて調製した)飽和硫酸ナトリウム溶液を45分間かけてゆっくりと添加した。添加し終わった後、25Lの酢酸エチルを撹拌しながら30分間かけて添加した。得られた反応混合物を45分間かけてセライトパッドに通して濾過し、セライト床をさらに17Lの酢酸エチルで洗浄して、この残渣から全ての生成物を取り除いた。組み合わせた有機物を減圧下で濃縮した。残渣を15Lの酢酸エチルに溶解させ、有機層を水(2×7L)で洗浄し、硫酸ナトリウム(1.1Kg)上で乾燥させた。濾過後、有機層を減圧下で濃縮し、高真空下で乾燥させると、生成物のリノレイルアルコールがオイルとして得られた。粗収量=5.5Kg(理論収量=5.43Kg)。この生成物をさらに精製することなく次の工程で用いた。
アルゴン注入口とサーモウェルとが取り付けられたきれいな乾燥した200Lの全ガラス反応器に、45LのDCMと5.5Kgの工程1からの粗生成物とを充填した。この溶液に、11.5Lのトリエチルアミン、次いで0.252Kg(2.0mol)のDMAPを添加した。この溶液をドライアイス−アセトン混合物を用いて−10℃に冷却し、この冷えた反応塊に、塩化メシル(3.2L、41.3mol)のDCM(10L)溶液を、0℃未満の温度に保持しながら、3時間かけて少しずつ添加した。添加し終わった後、反応混合物を0℃で1時間撹拌し、その後、反応混合物のTLC(DCM中5%EtOAc;PMA染色)により、出発アルコールの完全な消失が示された。この反応混合物に、17Lの氷冷水を添加し、層を分離した。一番上の水性層を10LのDCMで再び洗浄し、この層を分離した。合わせた有機層を(2Lの濃HClを18LのRO水と混合して調製した)2×10Lの希塩酸、2×7.5Lの水および(11KgのNaClを10LのRO水に溶解させて調製した)10Lのブラインで洗浄した。有機層を分離し、Na2SO4(2.75Kg)上で乾燥させ、濾過した。有機層を減圧下で蒸発させ、真空乾燥させると、粗メシラートが淡黄色オイルとして得られた。粗収量=7.1Kg(理論収量=7.1Kg)。この材料をさらに精製することなく次の工程で用いた。1H NMR(CDCl3,400MHz) δ=5.42−5.21(m,4H),4.20(t,2H),3.06(s,3H),2.79(t,2H),2.19−2.00(m,4H),1.90−1.70(m,2H),1.06−1.18(m,18H),0.88(t,3H)。13C NMR(CDCl3) δ=130.76,130.54,128.6,128.4,70.67,37.9,32.05,30.12,29.87,29.85,29.68,29.65,29.53,27.72,27.71,26.15,25.94,23.09,14.60。MS。C19H36O3Sについて計算された分子量、計算値344.53、実測値343.52(M−H−)。
アルゴン注入口とサーモウェルとが取り付けられたきれいな乾燥した200Lの全ガラス反応器に、25LのDMFと7.1Kgの工程2からの粗生成物を充填した。この混合物をアセトン−ドライアイス混合物を用いて−10℃に冷却した。この撹拌混合物に、臭化リチウム(2.7Kg、31.0mol)のDMF溶液25Lを、0℃未満の反応温度を保持しながら、1.5時間かけて添加した。添加し終わった後、アリコートのTLC(ヘキサン中10%EtOAc、PMA染色)により、出発メシラートの完全な消失が示されるまで、反応混合物を45℃で18〜20時間撹拌した。反応混合物を70Lの水で希釈し、57Lのヘキサンで抽出した。水性層を2×10Lのヘキサンでさらに抽出し、合わせた有機層(約120L)を2×10Lの水および(14Kgの塩化ナトリウムを10Lの水に溶解させて調製した)1×10Lのブラインで再び洗浄した。得られた有機層(120L)を硫酸ナトリウム(4Kg)上で乾燥させ、減圧下で濃縮すると、粗生成物(6.5Kg)が得られた。この粗生成物を、ヘキサンを溶離液として用いて、60〜120メッシュのシリカゲルを用いるカラムクロマトグラフィーで精製した。純粋な生成物の濃縮により、5.5Kg(81%、3工程)の臭化物4が無色の液体として得られた。1H NMR(CDCl3,400MHz) δ=5.41−5.29(m,4H),4.20(d,2H),3.40(t,J=7Hz,2H),2.77(t,J=6.6Hz,2H),2.09−2.02(m,4H),1.88−1.00(m,2H),1.46−1.27(m,18H),0.88(t,J=3.9Hz,3H)。13C NMR(CDCl3) δ=130.41,130.25,128.26,128.12,34.17,33.05,31.75,29.82,29.57,29.54,29.39,28.95,28.38,27.42,27.40,25.84,22.79,14.28。
アルゴン注入口と還流冷却器とサーモウェルとが取り付けられたきれいな乾燥した200Lの全ガラス反応器を脱気し、アルゴンでパージした。反応器に277g(11.3mol)の活性マグネシウム、次いで1.5Lの無水エーテルを充填した。反応器を再び3回脱気し、アルゴンでパージした。臭化物4(2.5Kg、7.6mol)をアルゴン下で5Lの無水エーテルに溶解させ、この溶液1Lを反応器に添加し、次いで25mL(0.35mol)のジブロモメタンを添加した。反応器の内容物を、水浴を用いて40℃に加熱した(泡立ちが観察された後で還流し、グリニャール試薬生成の開始が示された)。反応開始後、加熱装置を反応器から取り外し、残りの4Lの臭化物を、混合物の穏やかな還流を維持しながら、2時間30分かけてゆっくりと添加した。添加し終わった後、反応混合物を再び1時間加熱還流し(浴温度45℃)、その後、反応混合物のアリコートを水でクエンチして、TLC(ヘキサン、PMA染色)で分析した。これにより、出発臭化物の完全な消失が示された。反応混合物を氷浴を用いて10℃未満に冷却し、ギ酸エチルのエーテル溶液(4Lのエーテル中275mL)を2時間30分かけて添加し、添加し終わった後、反応混合物を室温に温めて、1時間撹拌した。反応混合物を冷却して10℃に戻し、この混合物にアセトン(1.15L)をゆっくりと添加し、次いで、7Lの氷冷水と(3.4Lの硫酸を34Lの氷冷水で希釈して調製した)10%硫酸溶液とを添加した。生成物を3×10Lのエーテルで抽出し、合わせた有機層を10Lのブラインで洗浄し、硫酸ナトリウム(2Kg)上で乾燥させた。減圧下での有機層の濃縮により、粗生成物(2Kg)が、微量のO−ホルミル化生成物とともに、所要のジリノレイルアルコールの混合物として得られた。この粗生成物をTHF(4L)に再溶解させ、20Lのガラス反応器に充填した。これにNaOH溶液(0.934Kgを8Lの氷冷水に溶解させたもの)を添加し、内容物を65℃で18時間加熱した後、TLC(ヘキサン中10%エーテル)により、O−ホルミル化生成物が所要のジリノレイルメタノールに完全に変換されたことが示された。 反応混合物を冷却し、エーテル(3×4L)で抽出し、合わせた有機層を5Lのブラインで洗浄し、硫酸ナトリウム(4Kg)上で乾燥させた。濾過後、有機層を濃縮すると、粗生成物が得られた。このようにして得られた粗生成物を、ヘキサン中の4%エーテルを用いて、60〜120メッシュのシリカゲルを用いるカラムクロマトグラフィーで精製した。純粋な生成物画分の濃縮により、純粋な6(1.45Kg、80%)が無色の液体として得られた。NMR(400MHz,CDCl3) δ5.47−5.24(m,8H),3.56(dd,J=6.8,4.2,IH),2.85−2.66(m,4H),2.12−1.91(m,9H),1.50−1.17(m,46H),0.98−0.76(m,6H)。13C NMR(101MHz,CDCl3) δ130.41,130.37,128.18,128.15,77.54,77.22,76.91,72.25,37.73,31.75,29.94,29.89,29.83,29.73,29.58,29.53,27.46,27.43,25.89,25.86,22.80,14.30。
ジリノレイルメタノール6(144g、272mmol)を1Lのジクロロメタンに溶解させ、それにジメチルアミノ酪酸7(55g、328mmol)の塩酸塩を添加し、次いでジイソプロピルエチルアミン(70mL)とDMAP(4g)とを添加した。周囲温度で5分間撹拌した後、EDCI(80g、417mmol)を添加し、反応混合物を室温で一晩撹拌した後、TLC(シリカゲル、CH2Cl2中5%MeOH)分析により、出発アルコールの完全な消失が示された。反応混合物をCH2Cl2(500mL)で希釈し、飽和NaHCO3(400mL)、水(400mL)およびブライン(500mL)で洗浄した。合わせた有機層を無水Na2SO4上で乾燥させ、溶媒を真空中で除去した。このようにして得られた粗生成物(180g)をフラッシュカラムクロマトグラフィー[以下の溶離液を用いた、2.5Kgシリカゲル、すなわち、i)0.1%NEt3を含むDCM 6Lを詰めたカラム;充填後、ii)0.1%NEt3を含むDCM 4L;iii)2%のMeOHと98%の0.1%NEt3を含むDCM 16L;iv)2.5%のMeOHと97.5%の0.1%NEt3を含むDCM 4L;v)3%のMeOHと97%の0.1%NEt3を含むDCM 12L]で精製すると、純粋な生成物8(MC3、159g、91%)が無色のオイルとして単離された。1H NMR(400MHz,CDCl3):δ5.46−5.23(m,8H),4.93−4.77(m,1H),2.83−2.66(m,4H),2.37−2.22(m,4H),2.20(s,6H),2.10−1.96(m,9H),1.85−1.69(m,2H),1.49(d,J=5.4,4H),1.39−1.15(m,39H),0.95−0.75(m,6H)。13C NMR(101MHz,CDCl3):δ173.56,130.38,130.33,128.17,128.14,77.54,77.22,76.90,74.44,59.17,45.64,34.36,32.69,31.73,29.87,29.76,29.74,29.70,29.56,29.50,27.44,27.41,25.84,25.55,23.38,22.78,14.27。EI−MS(+ve):C43H79NO2のMW計算値(M+H)+:642.6、実測値:642.6。
事前形成小胞の方法を用いてカチオン性脂質含有粒子を作製した。カチオン性脂質、DSPC、コレステロールおよびPEG−脂質を、それぞれ、40/10/40/10というモル比でエタノールに可溶化した。この脂質混合物を水性緩衝液(5OmMクエン酸塩、pH4)に添加し、それぞれ、30%(vol/vol)および6.1mg/mLという最終的なエタノールおよび脂質の濃度になるように混合して、押出しの前に室温で2時間平衡化させておいた。Nicomp分析で測定したときに70〜90nmの小胞直径が得られるまで、Lipex Extruder(Northern Lipids,Vancouver,BC)を用いて22℃で2つの積層された80nm孔径フィルター(Nuclepore)に通して、水和した脂質を押し出した。これには通常、1〜3回の通過を要した。小さい小胞を形成しないいくつかのカチオン性脂質混合物の場合、脂質混合物をより低いpHの緩衝液(50mMクエン酸塩、pH3)で水和してDSPC頭部基上のリン酸基をプロトン化することにより、安定な70〜90nmの小胞の形成が促進された。
式Iのカチオン性脂質のpKaを、水中では非蛍光性であるが、膜に結合したときに感知できるほどに蛍光性になる蛍光プローブである2−(p−トルイジノ)−6−ナフタレンスルホン酸(TNS)を用いて、本質的に記載されている通りに決定した(Eastman et al 1992 Biochemistry 31:4262−4268)。カチオン性脂質/DSPC/CH/PEG−c−DOMG(40:10:40:10モル比)から構成された小胞を、2〜11の範囲の様々なpHの緩衝液(130mM NaCl、10mM CH3COONH4、10mM MES、10mM HEPES)に希釈して0.1mMにした。この希釈した小胞にTNS水溶液(最終1μM)のアリコートを添加し、30秒間の平衡化期間の後、TNS含有溶液の蛍光を、それぞれ、321nmおよび445nmの励起波長および放出波長で測定した。測定された蛍光を溶液のpHに対してプロットし、データを市販のグラフ作成プログラムIgorProを用いてシグモイド曲線に対してフィッティングすることによって、カチオン性脂質含有小胞のpKaを決定した。式Iのカチオン性脂質のpKa滴定曲線を図10に示す。
Claims (10)
- 式Iの化合物または薬学的に許容されるその塩を提供する条件下で、ジリノレイルメタノールをジメチルアミノ酪酸の塩酸塩と反応させる、請求項1に記載の方法。
- EDCI、DMAPおよびDIPEAを含む条件下で、ジリノレイルメタノールをジメチルアミノ酪酸の塩と反応させる、請求項1に記載の方法。
- 式Iの化合物または薬学的に許容されるその塩を精製する工程をさらに含む、請求項1から3の何れか一項に記載の方法。
- フラッシュカラムクロマトグラフィーを用いて、式Iの化合物または薬学的に許容されるその塩を精製する、請求項4に記載の方法。
- 臭化リノレイルをジリノレイルメタノールに変換することによって、ジリノレイルメタノールを提供する工程をさらに含む、請求項1から5のいずれか一項に記載の方法。
- 前記変換が、臭化リノレイルをマグネシウムと反応させた後に、水と反応させることによって実施され、ジリノレイルメタノールを含む混合物が提供される、請求項6に記載の方法。
- 前記混合物を塩基と反応させて、ジリノレイルメタノールを提供する工程を更に含む、請求項7に記載の方法。
- ジリノレイルメタノールを精製する工程をさらに含む、請求項8に記載の方法。
- カラムクロマトグラフィーを用いて、ジリノレイルメタノールを精製する、請求項9に記載の方法。
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