JP4764426B2 - カチオン性脂質および使用方法 - Google Patents
カチオン性脂質および使用方法 Download PDFInfo
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- JP4764426B2 JP4764426B2 JP2007526138A JP2007526138A JP4764426B2 JP 4764426 B2 JP4764426 B2 JP 4764426B2 JP 2007526138 A JP2007526138 A JP 2007526138A JP 2007526138 A JP2007526138 A JP 2007526138A JP 4764426 B2 JP4764426 B2 JP 4764426B2
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Description
本出願は、2004年6月7日出願の米国仮特許出願第60/578,075号、2004年9月17日出願の第60/610,746号および2005年5月9日出願の第60/679,427号の恩典を主張し、これらの出願それぞれがすべての主旨で全体として参照により本明細書に組み入れられる。
遺伝子治療を臨床的に有用にするために、効果的で安全な遺伝子送達システムが求められている。ウイルスベクターは、比較的効率のよい遺伝子送達システムであるが、野生型への復帰ならびに免疫応答への懸念など、様々に制限される欠点がある(Worgall, et al., Human Gene Therapy 8:37-44 (1997)(非特許文献1); Peeters, et al., Human Gene Therapy 7: 1693-1699 (1996)(非特許文献2); Yei, et al., Gene Therapy 1:192-200 (1994)(非特許文献3); Hope, et al., Molecular Membrane Biology 15:1-14 (1998)(非特許文献4))。プラスミドDNA-カチオン性リポソーム複合体は、現在最も一般的に使用されている非ウイルス遺伝子送達ビークルである(Felgner, Scientific American 276:102-106 (1997)(非特許文献5); Chonn, et al., Current Opinion in Biotechnology 6:698-708 (1995)(非特許文献6))。しかし、複合体は、全身適用には不適な、大型の、画定度の低いシステムであり、さらに毒性の強い副作用を誘発することがある(Harrison, et al., Biotechniques 19:816-823 (1995)(非特許文献7); Huang, et al., Nature Biotechnology 15:620-621 (1997)(非特許文献8); Templeton, et al., Nature Biotechnology 15:647-652 (1997)(非特許文献9); Hofland, et al., Pharmaceutical Research 14:742-749 (1997)(非特許文献10))。
本発明は、一般的に使用されているカチオン脂質(DODACおよびDODMAなど)よりも高い柔軟性を有する新規なカチオン性脂質を提供する。より具体的には、驚くべきことに、本発明のカチオン性脂質は、リポソームまたはSPLPの膜流動性を上げることによって、リポソームならびに核酸脂質粒子(SPLP)の特性が高まり、それによってリポソームおよびSPLP内の生物活性薬剤の送達効率が上がることが見いだされている。特に、本発明は、下記の構造を有する式Iの化合物を提供する:
I. 序
本発明は、一般に使用されているカチオン性脂質(DODACおよびDODMAなど)よりも高い柔軟性を有する新規カチオン性脂質を提供する。脂質小胞(例えばリポソーム、SPLPおよびSNALP)内に組み入れた場合、本明細書に記載のカチオン性脂質は高い融合性を付与する。
「脂質」という用語は、脂肪酸のエステルを含み、水に不溶性であるが多くの有機溶媒に溶解性であることを特徴とする、有機化合物の群を指すが、これに限定されない。それらは、通常少なくとも3つの部類に分けられる:(1)脂肪および油ならびにロウを含む「単純脂質」;(2)リン脂質および糖脂質を含む「複合脂質」;(3)ステロイドなどの「誘導脂質」。
本発明は、一般に使用されているカチオン性脂質(DODACおよびDODMAなど)よりも高い柔軟性を有する新規カチオン性脂質を提供する。より具体的には、本発明は、下記の構造を有する式Iの新規カチオン性脂質を提供する:
一つの態様では、本発明は、本発明のカチオン性脂質、即ち式I、式IIの脂質またはそれらの組み合わせを含む、安定化核酸脂質粒子(SPLPまたはSNALP)およびその他の脂質ベースのキャリアシステム(例えばリポソーム、ミセル、ビロソーム、脂質-核酸粒子、核酸複合体、およびそれらの混合物)を提供する。本発明の脂質-核酸粒子は、典型的には、核酸、式Iまたは式IIのカチオン性脂質、非カチオン性脂質およびPEG脂質複合体を含む。式Iまたは式IIのカチオン性脂質は、典型的には、該粒子中に存在する全脂質の約2%〜約60%、約5%〜約50%、約10%〜約45%、約20%〜約40%または約30%を含む。非カチオン性脂質は、典型的には、該粒子内に存在する全脂質の約5%〜約90%、約10%〜約85%、約20%〜約80%、約30%〜約70%、約40%〜約60%または約48%を含む。PEG脂質複合体は、典型的には、該粒子中に存在する全脂質の約1%〜約20%、約1.5%〜約18%、約4%〜約15%、約5%〜約12%または約2%を含む。本発明の核酸脂質粒子は、さらにコレステロールを含んでよい。コレステロールは、存在する場合、典型的には、該粒子中に存在する全脂質の約10%〜約60%、約12%〜約58%、約20%〜約55%または約48%を含む。核酸脂質粒子の成分比は、例えば本明細書に記載のERPアッセイを用いた場合に変わるかもしれないことは、当業者は容易に理解できるだろう。例えば、全身送達の場合、カチオン性脂質は該粒子中に存在する全脂質の約5%〜約15%を含み、また局所もしくは局部送達の場合には、カチオン性脂質は該粒子中に存在する全脂質の約40%〜約50%を含むだろう。
式IおよびIIのカチオン性脂質は、単独で、または一もしくは複数のその他カチオン性脂質種もしくは非カチオン性脂質種と組み合わせるかのいずれかで、本発明に用いることができる。
本発明に用いる非カチオン性脂質は、安定した複合体を産生できる、様々ある中性の、非荷電性の、双極性またはアニオン性脂質のいずれかであり得る。それらは、好ましくは中性であるが、正または負に耐電していてもよい。本発明に有用である非カチオン性脂質の例としては次のものを含む:レシチン、ホスファチジルエタノールアミン、リゾレシチン、リゾホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、セファリン、カルジオリピン、ホスファチジン酸、セレブロシデス、ジセチルリン酸、ジステアロイルホスファチジルコリン(DSPC)、ジオレオイルホスファチジルコリン(DOPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジオレオイルホスファチジルグリセロール(DOPG)、ジパルミトイルホスファチジルグリセロール(DPPG)、ジオレオイルホスファチジルエタノールアミン(DOPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、パルミトイルオレオイル-ホスファチジルエタノールアミン(POPE)およびジオレオイル-ホスファチジルエタノールアミン4-(N-マレイミドメチル)-シクロヘキサン-1-カルボキシラート(DOPE-mal)、ジパルミトイルホスファチジルエタノールアミン(DPPE)、ジミリストイルホスホエタノールアミン(DMPE)、ジステアロイル-ホスファチジル-エタノールアミン(DSPE)、16-0-モノメチルPE、16-0-ジメチルPE、18-1-トランスPE、1-ステアロイル-2-オレオイル-ホスファチジエタノールアミン(SOPE)などのリン脂質関連物質。コレステロールなどの非カチオン性脂質またはステロールが存在してもよい。脂質を含んでいる追加の非リン酸は、例えばステアリルアミン、ドデシルアミン、ヘキサデシルアミン、パルミチン酸アセチル、グリセロールリシノール酸、ヘキサデシルステアラート、イソプロピルミリスチン酸、両性アクリルポリマー、トリエタノールアミン硫酸ラウリル、アルキル硫酸アリールポリオキシエチレン脂肪酸アミド、ジオクタデシル臭化ジメチルアンモニウム等、ジアシルホスファチジルコリン、ジアシルホスファチジルエタノールアミン、セラミド、スフィンゴミエリン、セファリンおよびセレブロシデスである。リソホスファチジルコリンおよびリソホスファチジルエタノールアミンのような他の脂質も存在してよい。非カチオン性脂質はさらに、同時係属中の米国特許出願第08/316,429号に記載されている、リン脂質またはセラミド(PEG-Cerと呼ばれる)と複合体を形成するPEG 2000、PEG 5000およびポリエチレングリコールなどのポリエチレングリコールをベースとしたポリマーも含む。
カチオン性および非カチオン性脂質に加えて、本発明のSPLPは、ATTA脂質、または、例えば国際公開公報第第05/026372号に記載のジアルキルオキシプロピルに結合したPEG(PEG-DAA)、例えば米国特許公開第20030077829号および第2005008689号に記載のジアシルグリセロールに結合したPEG(PEG-DAG)、ホスファチジルエタノールアミン(PE)に結合したPEG(PEG-PE)、またはセラミドに複合したPEG、あるいはそれらの混合物(米国特許第5,885,613を参照されたい)などのPEG脂質といった二重層安定化構成成分(BSC)を含む。一つの好ましい態様では、SPLPの凝集を阻止するBSCは、複合脂質である。好適な複合脂質としては、PEG脂質複合体、ATTA脂質複合体、カチオン性ポリマー脂質複合体(CPL)またはそれらの混合物を含むが、これらに限定されない。一つの好ましい態様では、SPLPは、PEG脂質複合体またはATTA脂質複合体のいずれかを、CPLと一緒に含む。
式中、Rは、水素、アルキルおよびアシルからなる群より選択されたメンバーであり;R1は、水素およびアルキルからなる群より選択されるメンバーであるか;または任意で、RおよびR1、ならびにそれらが結合する窒素は、アジド部分を形成し;R2は、水素、任意で置換されているアルキル、任意で置換されているアリール、およびアミノ酸の側鎖から選択さる群のメンバーであり;R3は、水素、ハロゲン、ヒドロキシ、アルコキシ、メルカプト、ヒドラジノ、アミノおよびNR4R5からなる群より選択されるメンバーであり、ここで、R4およびR5は、独立に水素またはアルキルであり;nは、4〜80であり;mは、2〜6であり;pは、1〜4であり;およびqは、0または1である。他のポリアミドが本発明の化合物に使用できることは、当業者には明らかであろう。
A-W-Y (VII)
式中、A、WおよびYは、下記の通りである。
上記成分に加えて、本発明のSPLPおよびSNALPは、核酸(例えば単鎖または二本鎖DNA、単鎖または二本鎖RNA、RNAi、siRNA等)を含む。好適な核酸としては、プラスミド、アンチセンスオリゴヌクレオチド、リボザイムならびにその他ポリヌクレオチドおよびオリゴヌクレオチドを含むが、それらに限定されない。好ましい態様では、核酸は、関心対象の生成物、例えば治療用生成物をコードする。本発明のSPLPおよびSNLPを用いて、核酸を、例えば核酸の発現、または細胞が発現する標的配列をサイレンシングするために、細胞(例えば哺乳動物内の細胞)に送達することができる。
関心対象の遺伝子としては、ウイルスの感染および生存に関連する遺伝子、代謝性疾患および障害(例えば肝臓の疾患および障害)と関連する遺伝子、腫瘍形成および細胞の形質転換と関連する遺伝子、血管形成遺伝子、炎症および自己免疫応答に関連する遺伝子のような免疫調節遺伝子、リガンドレセプター遺伝子、ならびに神経退行障害に関連する遺伝子を含むが、これらに限定されない。
ウイルスの感染および生存に関連する遺伝子としては、細胞に結合し、その中に侵入して複製するために、ウイルスが発現する遺伝子を含むが、これらに限定されない。特に関心の高いものは、慢性ウイルス疾患に関連するウイルス配列である。特に関心の高いウイルス配列としては、肝炎ウイルスの配列(Hamasaki, et al., FEBS Lett. 543:51 (2003); Yokota, et al., EMBO Rep. 4:602(2003); Schlomai, et al., Hepatology 37:764 (2003); Wilson, et al., Proc. Natl. Acad. Sci. 100:2783 (2003); Kapadia, et al., Proc. Natl. Acad. Sci. 100:2014 (2003); およびFIELDS VIROLOGY (Knipe et al. eds. 2001))、ヒト免疫不全ウイルス(HIV) (Banerjea, et al., Mol. Ther. 8:62 (2003); Song, et al., J. Virol. 77:7174 (2003); Stephenson JAMA 289:1494 (2003); Qin, et al., Proc. Natl. Acad. Sci. 100:183 (2003))、ヘルペスウイルス(Jia, et al., J. Virol. 77:3301 (2003))、ならびにヒト乳頭腫ウィルス(HPV) (Hall, et al., J. Virol. 77:6066 (2003); Jiang, et al., Oncogene 21:6041 (2002))を含む。サイレンシングできる例示的な肝炎ウイルス核酸配列としては、転写および翻訳に関与する核酸配列(例えばEn1、En2、X、P)、構造タンパク質(例えばCおよびC関連タンパク質;カプシドならびにS、M、および/もしくはLタンパク質を含むエンベロープタンパク質、またはその断片)をコードする核酸配列(例えば、前記、FIELDS VIROLOGY, 2001を参照されたい)。サイレンシング可能な例示的なC型肝炎核酸配列としては:セリンプロテアーゼ(例えばNS3/NS4)、ヘリカーゼ(例えばNS3)、ポリメラーゼ(例えばNS5B)ならびにエンベロープタンパク質(例えばE1、E2およびp7)を含むが、これらに限定されない。A型肝炎核酸配列は、例えばGenbankアクセッション番号NC_001489に記載されている;B型肝炎ウイルス核酸配列は、例えばGenbankアクセッション番号NC_003977に記載されている;C型肝炎ウイルス核酸配列は、例えばGenbankアクセッション番号NC_004102に記載されている;D型肝炎ウイルス核酸配列は、例えばGenbankアクセッション番号NC_001653に記載されている;E型肝炎ウイルス核酸配列は、例えばGenbankアクセッション番号NC_001434に記載されている;およびG型肝炎ウイルス核酸配列は、Genbankアクセッション番号NC_001710に記載されている。
代謝性疾患および障害(例えば肝臓が標的となる障害、ならびに肝疾患および障害)に関連する遺伝子としては、例えば異脂肪血症(例えば肝臓Xレセプター(例えばLXRαおよびLXRβ Genbankアクセッション番号 NM_007121)、ファルネソイドXレセプター(FXR)(GenbankアクセッションNM_005123、ステロール調節エレメント結合タンパク質(SREBP)、Site-1プロテアーゼ(S1P)、3-ヒドロキシ-3-メチルグルタリル補酵素A還元酵素(HMG補酵素A還元酵素)、アポリポプロテイン(ApoB)、およびアポリポプロテイン(ApoE))、ならびに糖尿病(例えばグルコース6-ホスファターゼ)で発現している、例えば遺伝子を含む(例えば、Forman et al., Cell 81:687 (1995); Seol et al., Mol. Endocrinol. 9:72 (1995), Zavacki et al., PNAS USA 94:7909 (1997); Sakai, et al., Cell 85:1037-1046 (1996); Duncan, et al., J. Biol. Chem. 272:12778-12785 (1997); ,Willy, et al., Genes Dev. 9(9):1033-45 (1995); Lehmann, et al., J. Biol. Chem. 272(6):3137-3140 Janowski, et al., Nature 383:728-731 (1996); Peet, et al., Cell 93:693-704 (1998)を参照されたい)。当業者は、代謝性疾患および障害(例えば肝臓が標的となる障害、ならびに肝疾患および障害)が、肝臓自体で発現している遺伝子だけでなく、他の器官および組織で発現している遺伝子も含むことに気づくだろう。
腫瘍形成および細胞形質転換に関連する遺伝子配列の例は、下記を含む:MLL融合遺伝子、BCR-ABL(Wilda, et al., Oncogene, 21:5716 (2002); Scherr, et al., Blood 101:1566)、TEL-AML1、EWS-FLI1、TLS-FUS、PAX3-FKHR、BCL-2、AML1-ETOおよびAML1-MTG8 (Heidenreich, et al., Blood 101:3157 (2003))などの転座配列; 多剤耐性遺伝子(Nieth, et al., FEBS Lett. 545:144 (2003); Wu, et al, Cancer Res. 63:1515 (2003))、サイクリン(Li, et al., Cancer Res. 63:3593 (2003); Zou, et al., Genes Dev. 16:2923 (2002))、β-カテニン(Verma, et al., Clin Cancer Res. 9:1291(2003))、テロメラーゼ遺伝子(Kosciolek, et al., Mol Cancer Ther. 2:209 (2003))、c-MYC、N-MYC、BCL-2、ERBB1およびERBB2 (Nagy, et al. Exp. Cell Res. 285:39 (2003))などの過剰発現配列;ならびにRAS(Tuschl and Borkhardt, Mol. Interventions, 2:158 (2002)に概説されている)などの変異配列。例えば、DNA修復酵素をコードする配列のサイレンシングは、化学療法薬の投与と組み合わせて用いられる(Collins, et al., Cancer Res. 63:1550 (2003))。腫瘍移動と関連するタンパク質をコードする遺伝子もまた、関心対象の標的配列であり、例えばインテグリン、セクレンおよび金属プロテアーゼである。前記の例は限定的ではない。腫瘍形成または細胞の形質転換、腫瘍の増殖あるいは腫瘍の移動を容易にし、または促進する遺伝子の任意の全配列または部分配列も、関心対象の遺伝子配列に含めることができる。
血管形成遺伝子は、新規の血管の形成を促進できる。特に関心の対象となるものは、血管内皮成長因子(VEGF) (Reich, et al., Mol. Vis. 9:210 (2003))またはVEGFrである。VEGFrを標的とするsiRNA配列は、例えば、英国特許第2396864号;米国特許公開第20040142895号;およびカナダ特許第2456444号に記載されている。
免疫調節遺伝子は、一つまたは複数の免疫応答を調節する遺伝子である。免疫調節遺伝子の例としては、成長因子(例えばTGF-α、TGF-β、EGF、FGF、IGF、NGF、PDGF、CGF、GM-CSF、SCF等)、インターロイキン(例えばIL-2、IL-3、IL-4、IL-6、IL-7、IL-10、IL-12、IL-15、IL-20等)、インターフェロン(例えばIFN-α、IFN-β、IFN-γ等)、TNF(例えばTNF-α)およびFlt3-リガンドなどのサイトカインを含む。FasおよびFasリガンド遺伝子もまた関心対象の免疫調節標的配列である(Song, et al., Nat. Med. 9:347 (2003))。造血細胞およびリンパ細胞の二次シグナル伝達分子をコードする遺伝子もまたは本発明に含まれ、例えばブルトンのチロシンキナーゼ(Btk)のようなTecファミリーキナーゼがある(Heinonen, et al., FEBS Lett. 527:274(2002))。
細胞レセプターリガンドとしては、細胞表面レセプター(例えばインスリンレセプター、EPOレセプター、G-タンパク質共役レセプター、チロシンキナーゼ活性を有するレセプター、サイトカインレセプター、成長因子レセプター等)に結合し、レセプターが関与する生理学的経路(例えばグルコースレベル調節、血液細胞の発生、有糸分裂誘発等)を調節(例えば阻害する、活性化する等)できるリガンドを含む。細胞レセプターリガンドの例としては、サイトカイン、成長因子、インターロイキン、インターフェロン、エリスロポイエチン(EPO)、インスリン、グルカゴン、Gタンパク質共役レセプターリガンド等が挙げられる。トリヌクレオチドリピート(例えばCAGリピート)拡張部をコードする鋳型は、脊髄延髄性筋萎縮症およびハンチントン病などのトリヌクレオチドリピート拡張部が引き起こす神経退行性障害での病原配列のサイレンシングに用いることができる(Caplen et al., Hum. Mol. Genet. 11:175 (2002))。
腫瘍抑制遺伝子とは、細胞、特に腫瘍細胞の増殖を阻止できる遺伝子である。それゆえに、腫瘍細胞へのこれら遺伝子の送達は、癌の治療に有用である。腫瘍抑制遺伝子としては、p53 (Lamb et al., Mol. Cell. Biol. 6:1379-1385 (1986), Ewen et al., Science 255:85-87 (1992), Ewen et al. (1991) Cell 66:1155-1164, and Hu et al., EMBO J. 9:1147-1155(1990))、RB1 (Toguchida et al. (1993) Genomics 17:535-543)、WT1 (Hastie, N. D., Curr. Opin. Genet. Dev. 3:408-413 (1993))、NF1 (Trofatter et al., Cell 72:791-800 (1993), Cawthon et al., Cell 62:193-201 (1990))、VHL (Latif et al., Science 260:1317-1320 (1993))、APC (Gorden et al., Cell 66:589-600 (1991))、DAPキナーゼ(例えばDiess et al. (1995) Genes Dev. 9:15-30を参照されたい)、p16 (例えばMarx (1994) Science 264 (5167):1846を参照されたい)、ARF (例えばQuelle et al. (1995) Cell 83(6):993-1000を参照されたい)、ニューロフィブロミン(例えばHuynh et al. (1992) Neurosci. Lett. 143(1-2):233-236を参照されたい)ならびにPTEN (例えばLi et al. (1997) Science 275 (5308):1943-1947を参照されたい)が含むが、これらに限定されない。
細胞毒性/自殺遺伝子は、細胞を直接または間接的に殺すことができる、アポトーシスを誘発できるかまたは細胞周期で細胞を抑止できる遺伝子である。このような遺伝子としては、免疫毒素、単純ヘルペスウイルス・チミジンキナーゼ(HSV-TK)、シトシンデアミナーゼ、キサンチン-グアニンホスホリボシルトランスフェラーゼ、p53、プリンヌクレオシドホスホリラーゼ、カルボキシエステラーゼ、デオキシシチジンキナーゼ、ニトロリダクターゼ、チミジンホスホリラーゼおよびチトロームp450 2B1の遺伝子を含むが、それらに限定されない。
いくつかの態様では、核酸はsiRNAである。siRNAは、関心対象の遺伝子の翻訳(即ち発現)をダウンレギュレーションまたはサイレンシングするのに用いることができる。好適なsiRNA配列は、当技術分野において周知の任意の手段を使用して同定され得る。典型的には、Elbashir et al., Nature 411:494-498 (2001)およびElbashir et al., EMBO J 20:6877-6888 (2001)に記載された方法を、ReynoldsらNature Biotech. 22 (3):326-330 (2004)に説明された合理的設計規則と組み合わせる。
siRNAは、例えば一つまたは複数の、単離された低分子干渉RNA(siRNA)二重鎖、より長い二本鎖RNA(dsRNA)などの、またはDNAプラスミド内の転写カセットから転写されたsiRNAまたはdsRNAのような形を含む、複数の形で提供できる。siRNAは、化学的に合成してもよい。好ましくは合成または転写されたsiRNAは、約1〜4ヌクレオチド、好ましくは約2〜3ヌクレオチドの3'オーバーハング、および5'リン酸基末端を有する。siRNA配列は、オーバーハングを有しても(例えば(Elbashir et al., Genes Dev. 15:188 (2001); Nykanen, et al., Cell 107:309 (2001)に記載の3'または5'オーバーハング)、あるいはオーバーハングを欠いてもよい(即ち、平滑末端を有する)。
本発明は、プラスミドまたはその他の核酸を脂質二重層に封入し、分解から保護する、血清安定核酸脂質粒子を調製する方法を提供する。本発明の方法で作成した粒子は、典型的には約50nm〜約150nm、より典型的には約100nm〜約130nm、最も典型的には約110nmから約115nmの大きさを有する。粒子は、連続混合法、界面活性剤透析法、または有機溶媒を利用し、成分混合中に単相を提供する逆相法の改良法を含むが、これに限定されない本技術分野で公知の任意の方法によって形成できる。
(a)界面活性剤溶液中で核酸とカチオン性脂質を合わせ、被覆核酸脂質複合体を形成する段階;
(b)非カチオン性脂質を被覆核酸脂質複合体と接触させて、核酸脂質複合体および非カチオン性脂質を含む界面活性剤溶液を形成する段階;ならびに
(c)段階(b)の界面活性剤溶液を希釈して、核酸が脂質二重層内に封入されており、粒子が血清安定的であり、かつ約50〜約150nmの大きさを有する血清安定核酸脂質粒子の溶液を提供する段階。
(a)有機溶媒中のカチオン性脂質および非カチオン性脂質を含む混合液を調製する段階;
(b)核酸の水溶液を、段階(a)の該混合液と接触させて、清澄な単相を提供する段階;ならびに
(c)該有機溶媒を除去して、該核酸が脂質二重層に封入されており、かつ該粒子が血清安定でかつ約50〜約150nmの大きさを有する核酸脂質粒子の懸濁液を提供する段階。
(a)核酸を、非カチオン性脂質および界面活性剤を含む溶液と接触させて核酸脂質混合液を形成する段階;
(b)カチオン性脂質を核酸脂質混合液と接触させて、核酸の負の電荷部分を中和し、核酸および脂質の電荷中和混合液を形成する段階;ならびに
(c)電荷中和混合液から界面活性剤を除去して、核酸が分解から保護されている核酸脂質粒子の溶液を提供する段階。
(a)溶液中で、ある量のカチオン性脂質を核酸と接触させ、疎水性の核酸脂質複合体を提供する段階:溶液は、約15〜35%の水、約65〜85%の有機溶媒、および約0.85〜約2.0の+/-電荷比を生ずるのに十分な量のカチオン性脂質を含む;
(b)溶液中で、疎水性の核酸脂質複合体を、非カチオン性脂質と接触させ、核酸脂質混合液を提供する段階;ならびに
(c)核酸脂質混合液から有機溶媒を除去して、分解から核酸が保護されている核酸脂質粒子を提供する段階。
本発明の核酸脂質粒子は、単独で、または投与経路および標準的な医薬的慣行に従って選択された、生理学的に許容される担体(生理学的食塩水またはリン酸緩衝液)との混合物中のいずれかで投与できる。一般的には、標準の生理食塩水が薬学的に許容される担体として用いられるであろう。その他の好適な担体としては、例えば水、緩衝化水、0.4%食塩水、0.3%グリシン等を含み、かつ安定性を高めるために、アルブミン、リポタンパク質、グロブリンなどの糖タンパク質を含む。
上記SNALP調合物に加えて、本発明のカチオン性脂質(即ち、式Iまたは式IIのカチオン性脂質)を、空のリポソーム、または一もしくは複数の生物活性薬剤を含有するリポソームのいずれかの調製に用いることができる。
リポソームを調製するための種々な方法が、例えばSzoka et al., Ann. Rev. Biophys. Bioeng., 9:467 (1980)、米国特許第4,186,183号、第4,217,344号、第4,235,871号、第4,261,975号、第4,485,054号、第4,501,728号、第4,774,085号、第4,837,028号、第4,946,787号、国際公開公報第91/17424号、Deamer and Bangham, Biochim. Biophys. Acta, 443:629-634 (1976); Fraley et al., PNAS. USA, 76:3348-3352 (1979); Hope et al., Biochim. Biophys. Acta, 812:55-65 (1985); Mayer et al., Biochim. Biophys. Acta, 858:161-168 (1986); Williams et al., Proc. Natl. Acad. Sci., 85:242-246 (1988)、教本Liposomes, Marc J. Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1およびHope et al., Chem. Phys. Lip., 40:89 (1986)に記載のように利用可能である。好適な方法は、超音波処理、押出し、高圧/均質化、マイクロフルイダイゼーション、界面活性剤透析、小さなリポソーム小胞のカルシウム誘発融合およびエーテル注入法を含むがそれらに限定されず、その全ては当技術分野において周知である。
本発明の薬物送達組成物(例えばリポソーム、ミセル、脂質-核酸粒子、ビロゾーム等)は、治療薬または生物活性薬剤の全身または局所送達に有用であり、また診断アッセイにも有用である。
本発明のカチオン性脂質を用いて調製した薬物送達組成物、例えばリポソームは、腫瘍、炎症を起こした関節、障害等を含む様々な疾患状態の診断画像化を容易にするマーカーで標識できる。典型的には、これらの標識は、放射性マーカーであるが、蛍光標識も用いることができる。ガンマ線を放出する放射性同位元素の使用は、シンチレーションウェルカウンターで容易に測定でき、測定前に組織を均質化する必要がなく、またガンマカメラを使って画像化できることから、特に有利である。
通常の薬物をリポソーム内に付加する方法としては、例えば封入技術、二重層内挿入および膜電位差付加法がある。
発明を、以下の実施例を用いてより詳しく説明する。以下の実施例は例示を目的として提供するものであり、いかなる形でも、本発明を制限すること意図したものではない。当業者は、実質同一の結果を生ずる変更または改良が可能である、様々な重要でないパラメータを容易に認識すると考えられる。
材料:DPPS、1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)およびコレステロールは、Avanti Polar Lipid(Alabaster, AL)より購入した。TNSは、Sigma-Aldrich Canada(Oakville, ON)より得た。RiboGreenは、Molecular Probes(Eugene, OR)より得た。アルキルメシレートは、Nu-Chek Prep, Inc. (Elysian, MN, USA)から購入した。siRNA(抗ルシフェラーゼおよびミスマッチコントロール)は、Dharmacon (Lafayette, CO, USA)より購入した。抗ルシフェラーゼセンス配列は、
であった。抗ルシフェラーゼアンチセンス配列は、
であった。他の化学薬品は、全てSigma-Aldrich (Oakville, ON, Canada)より購入した。
上記の技術に従って調合された脂質/核酸粒子は、様々な方法によって、血清安定性についてアッセイできる。
3-(ジメチルアミノ)-1,2-プロパンジオール(714mg、6mmol)および95%水素化ナトリウム(NaH、1.26g、50mmol)を、ベンゼン(30mL)中、窒素下で30分間撹拌した。リノレイルメシレート(5.0g、15mmol)を加え、反応物を窒素下で3時間、還流した。次に、反応混合物をエタノールをゆっくり添加してクエンチングしながら氷槽内で冷却した。さらに150mLのベンゼンでの希釈に続いて、混合物液を蒸留水(2×150mL)およびブライン(150mL)で洗浄した。有機相を硫酸マグネシウム上で乾燥させ、蒸発させて粗生成物を得た。粗生成物は、0〜5%のメタノールのクロロホルム溶液で溶離するシリカゲル(Kiesel Gel 60)カラムにかけ精製した。カラム分画を、薄層クロマトグラフィー(TLC)(シリカゲル、クロロホルム/メタノール 9:1 v/v、モリブデン酸塩浸漬により視覚化)により分析し、精製した生成物含有分画(Rf=0.5)を貯留および濃縮した。
本実施例は、本明細書記載のSNALP調合物の物理特性を示す。様々なカチオン性脂質を含有するSNALPを記載のようにして調製し、封入されたRNAおよび粒子サイズを評価した(下表1)。3種類の不飽和カチオン性脂質から、ほぼ同一サイズ(132〜140nm)の調合物が得られた。全ての調合物の多分散性は低く、粒子サイズの分布が狭いことを示した。最終粒子内へのRNA封入率は、合計で84〜85%であった。飽和脂質のDSDMAを用いて、SNALPへsiRNA封入を試みたところ、封入率67%の若干大型粒子(180nm)が形成された。
カチオン性脂質の見かけ上のpKaは、上記実施例1に記載のようにして決定された。我々の脂質pKa決定では、負の電荷を持つ、膜電位インジケータである(Bailey and Cullis, Biochemistry 33 12573-80 (1994))2-(p-トルイジノ)ナフタレン-6-硫酸を使用した。TNSは、正の荷電を有する膜に静電気的に引きつけられる。続いて脂質膜に吸着することにより、TNS付近の環境は急速により親油性となり、そうでない場合にはTNSの蛍光を消光する水分子を排除する。TNSは、正の電荷を有する膜ほど容易に吸着するため、TNSの蛍光は膜表面の正電荷のインジケータである。各SNALP調合物の表面pKa値は、TNS存在下に、局所pHを変化させることによって決定した。図5では、同様のpKa値(6.7〜7.0)を有する不飽和脂質を含有する調合物が、粒子が生理学的pHにおいては電荷的に中性であるが、エンドソームのpHでは正の電荷をもつようになることを示唆しているのが見て取れる。しかしながら、飽和脂質DSDMAは、約7.6というより高いpKaを持つ粒子を生成した。DSDMA含有SNALP粒子は、生理学的pHにおいて電荷を持つと予想された。
相転移温度に関する飽和の意義を、31P-NMRを用いて調べた。アニオン性リン脂質/カチオン性脂質混合物での脂質多形性は、この方法を用いて他の人々により検証されており、リン脂質内のリン酸基の存在により助長されている(Epand et al., Chem. Phys. Lipids 57 75-80 (1991)); Felgner et al., PNAS USA 84 7413-7417 (1987))。NMRトレースの形状は、脂質の配置に応じて変化する。二重層構造は、低いフィールドショルダーを持つ高いフィールドピークを生ずる。しかしながら、相転移温度(Tc)より上では、脂質は融合HII相を採択し、低フィールド側に現れるピークのパターンは逆転する。これまでに31P-NMR研究は、ある温度(相転移温度、Tc)より上では、脂質が融合HII相を採択することを示している[Epand et al., Chem. Phys. Lipids 57 75-80 (1991); Felgner et al., PNAS USA. 84 7413-7417 (1987)]。二重層(Lα相)から融合HII相への変換に、より高い温度が必要なことは、低融合性二重層であることを示している。変換が起こる温度を決定することによって、脂質がHII相を形成する相対容易度、即ちそれらの「融合性」を決定できる。
本実施例は、下記を含むSNALPによるNeuro2A細胞のインビトロトランスフェクション後の、核酸の発現を比較した実験を記載する:(1)DODAC、DODMAまたはDLinDMA;(2)PEG-C-DMA;および(3)SNALPに封入されたルシフェラーゼに対するsiRNA二重鎖(即ち、次の配列:
(SEQ ID NO:1)を含み、
(SEQ ID NO:3)に相補的はDNA配列を標的化するsiRNA)。Neuro2A細胞は、CMVプロモータ(pLO55)制御下にあるルシフェラーゼをコードするプラスミドで安定にトランスフェクションされた。次に、安定にトランスフェクトされた細胞を下記を含むSNALPでトランスフェクトした:15、20、25、30、35または40%のDODAC、DODMAまたはDLinDMA;2%のPEG-C-DMA、およびSNALPに封入されているルシフェラーゼに対するsiRNA二重鎖。SNALPによるトランスフェクション48時間後に、ルシフェラーゼタンパク質の発現を測定した。30%DLinDMAを含むSNALPは、DODACまたはDODMAを含むSNALPに比べ、Neuro2A細胞でのルシフェラーゼ発現をより効率的に低下させた。これらの結果は、図6に示す。
4種類のカチオン性脂質(即ち、DSDMA、DODMA、DLinDMAおよびDLenDNA)のそれぞれを含有するSNALPの、安定トランスフェクトNeuro2A細胞に遺伝子サイレンシングをもたらす能力について評価した。安定にトランスフェクトされ、ルシフェラーゼを発現しているNeuro2A細胞を、抗ルシフェラーゼsiRNAを含有するSNALPで、48時間処理した。遺伝子サイレンシング効率は、これら細胞に残存しているルシフェラーゼ活性を、ミスマッチsiRNAを含有するコントロールSNALPで処理した細胞に残存している該活性と比較することによって評価した。
本実施例は、15%DLinDMAを含むSPLPを用いた器官のインビボトランスフェクションを使用して、CMVプロモータの制御下のルシフェラーゼをコードするプラスミドを封入しているSPLPをNeuro2A腫瘍担持オスA/Jマウスに投与できることを証明する実験を記載する。SPLPの調合は下記の通りであった:
本実施例は、DLinDMAまたはDODMA、およびPEG-C-DMAを様々なパーセンテージ(15%、10%、5%または2.5%)で含むSPLPを用いて、器官のインビボトランスフェクションを証明する実験を記載する。ルシフェラーゼをコードするプラスミドを封入しているSPLPを、Neuro2A腫瘍担持オスA/Jマウスに投与した。SPLPの調合は下記の通りであった:
本実施例は、PEG-C-DMAを様々なパーセンテージで含む脂質小胞の血液クリアランス率を評価するために実施した実験を記載する。3H-CHE標識SPLP、SNALPまたは空小胞を、単一静脈投与量で、オスA/Jマウスに投与した。SPLPはカチオン性脂質のDODMAを含み、SNALPはカチオン性脂質DLinDMAを含んだ。脂質小胞の調合は下記の通りであった:
本実施例は、PEG-C-DMAを様々なパーセンテージで含む脂質小胞の生体内分布を評価するために実施した実験を記載する。3H-CHE標識SPLP、SNALPまたは空小胞を、単一静脈投与量で、Nuero 2A腫瘍担持オスA/Jマウスに投与した。SPLPはカチオン性脂質のDODMAを含み、SNALPはカチオン性脂質DLinDMAを含んだ。脂質小胞の調合は次の通りであった:
本実施例は、DLinDMAを含み、かつ抗ルシフェラーゼsiRNA配列を封入するSNALP投与後の、遠位部腫瘍での遺伝子サイレンシングを証明した実験を記載する。
(SEQ ID NO:1)を含み:
(SEQ ID NO:3)に相補的はDNA配列を標的化するsiRNA)を封入しているSNALPを、Neuro2A-G腫瘍担持A/Jマウスに静脈内投与した。SNALP調合物は下記の通りであった:
本実施例は、DLinDMAを含みかつ上記実施例3に記載の抗ルシフェラーゼsiRNA配列を封入しているSNALPと接触させた後の、哺乳動物細胞における遺伝子サイレンシングを証明する実験を記載する。Neuro2A細胞を、上記実施例3に記載のルシフェラーゼをコードするプラスミドで安定にトランスフェクトし、Neuro2A-G細胞を生成した。Neuro2A-G細胞を、SNALP調合物と24または48時間接触させた。SNALP調合物は、PEG-C-DLA(C12)またはPEG-C-DMA(C14)のいずれかを含み、かつ下記のものである:
本実施例は、DLinDMAを含み、上記実施例3に記載の抗ルシフェラーゼsiRNA配列を封入しているSNALPと接触させた後の、哺乳動物細胞における遺伝子サイレンシングを証明する実験を記載する。Neuro2A細胞を、上記実施例3に記載のルシフェラーゼをコードするプラスミドで安定にトランスフェクトし、Neuro2A-G細胞を生成した。Neuro2A-G細胞を、クロロキン存在下および非存在下で、SNALP調合物と48時間接触させた。SNALP調合物は、様々なパーセンテージのPEG-C-DMA(C14)、およびDODMAまたはDLinDMAのいずれかを含有した。調合は下記の通りであった:
調合物が細胞に取り込まれる量を、3H標識CHEを組み入れたSNALPを用いて測定した[Bally et al., in Liposome Technology, Vol. III, pp. 27-41, CRC Press (1993)]。Neuro2A細胞を、3H標識CHE含有SNALPで24時間処理した。3H-CHE測定前に、細胞を洗浄して、組み込まれなかったSNALPを取り除いた。取り込みは、細胞に与えた全活性のパーセンテージとして表されている。細胞の取り込みは、カチオン性脂質の飽和度の上昇に伴い増加する。誤差バーは、n=3での標準偏差を表す。結果は、図15に示す。
Claims (48)
- R3およびR4が同一である、請求項1記載の化合物。
- R3およびR4が、ドデカジエニル、テトラデカジエニル、ヘキサデカジエニル、リノレイルおよびイコサジエニルからなる群より独立に選択される、請求項1記載の化合物。
- R3およびR4が共にリノレイルである、請求項3記載の化合物。
- R3およびR4が共に不飽和部位を少なくとも3ヵ所含む、請求項1記載の化合物。
- R3およびR4が、ドデカトリエニル、テトラデカトリエニル、ヘキサデカトリエニル、リノレニルおよびイコサトリエニルからなる群より独立に選択される、請求項1記載の化合物。
- 非カチオン性脂質をさらに含む、請求項7記載のリポソーム。
- 非カチオン性脂質が、ジオレオイルホスファチジルエタノールアミン(DOPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、エッグホスファチジルコリン(EPC)、ジステアロイルホスファチジルコリン(DSPC)、パルミトイルオレヨールホスファチジルグリセロール(POPG)、ジパルミトイルホスファチジルエタノールアミン(DPPE)、ジミリストイルホスホエタノールアミン(DMPE)、ジステアロイル-ホスファチジル-エタノールアミン(DSPE)、16-O-モノメチルPE、16-O-ジメチルPE、18-1-トランスPE、パルミトイルオレオイル-ホスファチジルエタノールアミン(POPE)、1-ステアロイル-2-オレオイル-ホスファチジルエタノールアミン(SOPE)、コレステロールおよびそれらの混合物からなる群より選択されるメンバーである、請求項8記載のリポソーム。
- PEG脂質をさらに含む、請求項7記載のリポソーム。
- PEG脂質が、ポリエチレングリコール-ジアシルグリセロール(PEG-DAG)複合体、ポリエチレングリコール-ジアルキルオキシプロピル(PEG-DAA)複合体、PEG-セラミド、PEG-PE、およびそれらの混合物からなる群より選択される、請求項9記載のリポソーム。
- 生物活性薬剤をさらに含む、請求項7記載のリポソーム。
- 生物活性薬剤が、抗腫瘍薬、抗生物質、免疫調節薬、抗炎症剤、中枢神経系に作用する薬剤、ポリペプチド、および核酸からなる群より選択されるメンバーである、請求項12記載のリポソーム。
- 細胞に生物活性薬剤を送達するための薬剤を製造するための請求項7記載のリポソームの使用であって、該生物活性薬剤が該リポソーム内に封入されている使用。
- 前記細胞が哺乳動物である、請求項14記載の使用。
- カチオン性脂質が、1,2-ジリノレイルオキシ-N,N-ジメチルアミノプロパン(DLinDMA)および1,2-ジリノレニルオキシ-N,N-ジメチルアミノプロパン(DLenDMA)からなる群より選択される、請求項16記載の核酸脂質粒子。
- カチオン性脂質がDLinDMAである、請求項16記載の核酸脂質粒子。
- 非カチオン性脂質が、ジオレオイルホスファチジルエタノールアミン(DOPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、エッグホスファチジルコリン(EPC)、ジステアロイルホスファチジルコリン(DSPC)、パルミトイルオレヨールホスファチジルグリセロール(POPG)、ジパルミトイルホスファチジルエタノールアミン(DPPE)、ジミリストイルホスホエタノールアミン(DMPE)、ジステアロイル-ホスファチジル-エタノールアミン(DSPE)、16-O-モノメチルPE、16-O-ジメチルPE、18-1-トランスPE、パルミトイルオレオイル-ホスファチジルエタノールアミン(POPE)、1-ステアロイル-2-オレオイル-ホスファチジルエタノールアミン(SOPE)、コレステロールおよびそれらの混合物からなる群より選択されるメンバーである、請求項16記載の核酸脂質粒子。
- 非カチオン性脂質がDSPCである、請求項16記載の核酸脂質粒子。
- PEG脂質が、ポリエチレングリコール-ジアシルグリセロール(PEG-DAG)複合体、ポリエチレングリコール-ジアルキルオキシプロピル(PEG-DAA)複合体、PEG-セラミド、PEG-PEおよびそれらの混合物からなる群より選択されるメンバーである、請求項16記載の核酸脂質粒子。
- PEG脂質がPEG-DAA複合体である、請求項16記載の核酸脂質粒子。
- PEG-DAA複合体がPEG-ジミリスチルオキシプロピル(C14)である、請求項22記載の核酸脂質粒子。
- ステロールをさらに含む、請求項16記載の核酸脂質粒子。
- ステロールがコレステロールである、請求項24記載の核酸脂質粒子。
- 核酸が、DNA、RNA、siRNA、プラスミド、アンチセンスオリゴヌクレオチド、およびリボザイムからなる群より選択されるメンバーである、請求項16記載の核酸脂質粒子。
- 核酸が、関心対象の治療用生成物をコードする、請求項16記載の核酸脂質粒子。
- 関心対象の治療用生成物が、ポリペプチドおよび低分子干渉RNA (siRNA)からなる群より選択されるメンバーである、請求項27記載の核酸脂質粒子。
- 核酸脂質粒子内の核酸が、該粒子をヌクレアーゼに37℃で20分間曝露した後に実質的に分解しない、請求項16記載の核酸脂質粒子。
- 核酸が、核酸脂質粒子に完全に封入されている、請求項16記載の核酸脂質粒子。
- カチオン性脂質が、粒子中に存在する全脂質の2%〜60%を含む、請求項16記載の核酸脂質粒子。
- カチオン性脂質が、粒子中に存在する全脂質の5%〜45%を含む、請求項16記載の核酸脂質粒子。
- カチオン性脂質が、粒子中に存在する全脂質の15%〜40%を含む、請求項16記載の核酸脂質粒子。
- カチオン性脂質が、粒子中に存在する全脂質の30%を含む、請求項16記載の核酸脂質粒子。
- カチオン性脂質が、粒子中に存在する全脂質の40%〜50%を含む、請求項16記載の核酸脂質粒子。
- 非カチオン性脂質が、粒子中に存在する全脂質の5%〜90%を含む、請求項16記載の核酸脂質粒子。
- 非カチオン性脂質が、粒子中に存在する全脂質の20%〜85%を含む、請求項16記載の核酸脂質粒子。
- PEG脂質が、粒子中に存在する全脂質の1%〜20%を含む、請求項16記載の核酸脂質粒子。
- PEG脂質が、粒子中に存在する全脂質の4%〜15%を含む、請求項16記載の核酸脂質粒子。
- ステロールが、粒子中に存在する全脂質の10%〜60%を含む、請求項24記載の核酸脂質粒子。
- ステロールが、粒子中に存在する全脂質の20%〜45%を含む、請求項24記載の核酸脂質粒子。
- 請求項16記載の核酸脂質粒子および薬学的に許容される担体を含む、薬学的組成物。
- 核酸を細胞内に導入するための薬剤を製造するための、下記を含む核酸脂質粒子の使用:
(a) 下記の構造を有する式Iのカチオン性脂質:
式中:
R1およびR2は、C1〜C3アルキルであり;
R3およびR4は、10〜20個の炭素原子を有するアルキル基からなる群より独立に選択され、ここで、R3およびR4の両方が、不飽和部位を少なくとも2ヵ所含み、かつ、ドデカジエニル、ヘキサデカジエニル、リノレイル、イコサジエニル、ドデカトリエニル、テトラデカトリエニル、ヘキサデカトリエニル、リノレニルおよびイコサトリエニルからなる群から選択される;
(b)非カチオン性脂質;
(c)PEG脂質複合体;ならびに
(d)核酸。 - R 1 およびR 2 が、両方ともメチルである、請求項1記載の化合物。
- R 3 およびR 4 が、両方ともリノレニルである、請求項1記載の化合物。
- 前記化合物が、1,2-ジリノレイルオキシ-N,N-ジメチルアミノプロパン(DLinDMA)および1,2-ジリノレニルオキシ-N,N-ジメチルアミノプロパン(DLenDMA)からなる群から選択される、請求項1記載の化合物。
- 前記化合物が1,2-ジリノレイルオキシ-N,N-ジメチルアミノプロパン(DLinDMA)である、請求項1記載の化合物。
- 前記化合物が、1,2-ジリノレニルオキシ-N,N-ジメチルアミノプロパン(DLenDMA)である、請求項1記載の化合物。
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US57807504P | 2004-06-07 | 2004-06-07 | |
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AU (1) | AU2005251403B2 (ja) |
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AU2005251403B2 (en) | 2011-09-01 |
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JP2008501729A (ja) | 2008-01-24 |
CA2569645C (en) | 2014-10-28 |
US20110262527A1 (en) | 2011-10-27 |
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HK1103391A1 (en) | 2007-12-21 |
US20060083780A1 (en) | 2006-04-20 |
WO2005120152A2 (en) | 2005-12-22 |
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