JP6466500B2 - 多価rna−ナノ粒子組成物 - Google Patents
多価rna−ナノ粒子組成物 Download PDFInfo
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- JP6466500B2 JP6466500B2 JP2017082667A JP2017082667A JP6466500B2 JP 6466500 B2 JP6466500 B2 JP 6466500B2 JP 2017082667 A JP2017082667 A JP 2017082667A JP 2017082667 A JP2017082667 A JP 2017082667A JP 6466500 B2 JP6466500 B2 JP 6466500B2
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- polynucleotide
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- 150000008163 sugars Chemical class 0.000 description 1
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- 125000000565 sulfonamide group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
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- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
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Description
本発明は、National Cancer Institute/Centers of Cancer Nanotechnology Excellence(NCI/CCNE)によって付与された助成金第5U54 CA119341号、およびにNational Institutes of Health(NIH)よって付与された助成金第5DP1 OD000285号の下、政府の支援を受けてなされた。政府は、本発明に一定の権利を有する。
本発明は、二重鎖RNAを用いて機能化されたナノ粒子に関する。本発明はまた、RNAをナノ粒子に結合体化させる方法を提供する。
NP)を設計、合成、試験、および利用してきた[Mirkinら、「Nature」382:607(1996)]。こうした努力によって、ハイブリッドナノ構造についての新規の基本理解[Demersら、「Anal.Chem.」72:5535(2000);Jinら、「J.Am.Chem.Soc.」125:1643(2003);Lytton−Jeanら、「J.Am.Chem Soc」127:12754〜12754(2005);Storhoffら、「J.Am.Chem.Soc.」122:4640(2000);Youら、「Soft Matter」2:190(2006);Wangら、「Nanomed.」1:413(2006)]、重要でありかつ場合によっては商業的に実現可能である検出および診断アッセイ[Namら、「Science」301:1884(2003);Stoevaら、「J.Am.Chem.Soc.」128:8378(2006);Liuら、「J.Am.Chem.Soc.」126:12298(2004);Fauldsら、「Anal.Chem.」76:412(2004)]、およびDNAシントンの使用を介する材料組立をプログラムする能力[Mirkinら、「Nature」382:607(1996);Parkら、「Nature」451:553(2008);Nykypanchukら、「Nature」451:549(2008)]が得られてきた。多価DNA−Au NPには、融解温度の尖鋭化および上昇[Jinら、「J.Am.Chem.Soc.」125:1643(2003)]、結合特性の向上[Lytton−Jeanら、「J.Am.Chem Soc」127:12754−12754(2005)](同配列の遊離鎖と比較した場合)、および距離依存性光学特性[Elghanianら、「Science」277:1078(1997)]などのいくつかの独特な特性がある。多価分子系に関する研究[Gestwickiら、「J.Am.Chem.Soc.」124:14922(2002)]に同意するならば、ナノ粒子の、高い表面DNA密度や、多座配位相互作用に関わる能力が、こうした独特な特性の由来を提示するものである。
(a)約0.1M塩化ナトリウム(NaCl)を含む溶液中で、チオール化RNA二重鎖をナノ粒子と混合すること;
(b)先の溶液よりも増大した濃度のNaClをそれぞれ含む一連の塩溶液中で、混合物を熟成させること;
(c)混合物を超音波処理すること;および
(d)結合体化されたナノ粒子を調製すること。
多価粒子およびその並外れた特性を利用して、RNAを装填し、細胞膜を通過させるための方法は、今日まで開発されてこなかった。RNAに関する最も難しい問題の1つ、すなわち特にその化学的不安定性を克服する合成の経路および材料が開発される必要が、確かに存在する。
したがって、ポリヌクレオチドを付着させるために機能化されたナノ粒子が提供される。ナノ粒子のサイズ、形状、および化学組成は、得られるポリヌクレオチドで機能化されたナノ粒子の特性に寄与する。これらの特性には、例えば、光学特性、光電子特性、電気化学特性、電子特性、様々な溶液中での安定性、磁気特性、および細孔やチャネルのサイズの変動が含まれる。サイズ、形状、および/または化学組成が様々であるナノ粒子の混合物、ならびにサイズ、形状、および化学組成が一様であるナノ粒子、ひいてはこれらの特性の混合物の使用が企図される。適切な粒子の例としては、限定されないが、凝集粒子、等方性粒子(球状粒子など)、異方性粒子(非球状の棒状体、四面体、および/または角柱など)、およびコアシェル粒子(その開示全体が参照により組み込まれる米国特許第7,238,472号および国際公開第WO2003/08539号に記載されているものなど)が挙げられる。
したがって、二重鎖RNAがナノ粒子と結合するような、ポリヌクレオチドが付着されたナノ粒子が提供される。ある態様では、ナノ粒子と結合するRNAは、低分子干渉RNA(siRNA)である。二重鎖RNAとナノ粒子との様々な手段を介した結びつきが企図される。
センス 対 アンチセンス
ある態様では、ナノ粒子に付着されるRNAの鎖は、「センス」鎖であり、二重鎖RNAの相補鎖は、センス鎖とはハイブリッド形成するが、ナノ粒子には付着しない。他の態様では、ナノ粒子に付着されるRNAの鎖は、「アンチセンス」鎖であり、二重鎖RNAの相補鎖は、アンチセンス鎖とはハイブリッド形成するが、ナノ粒子には付着しない。本明細書で使用する場合、「センス」鎖は、標的ポリヌクレオチドと同一の鎖であり、「アンチセンス」鎖は、標的ポリヌクレオチドと相補的な鎖である。センス鎖またはアンチセンス鎖のナノ粒子への付着によって、二本鎖RNAのナノ粒子に対する方向性の一態様が決定される。
ある実施形態では、ナノ粒子に付着されるポリヌクレオチドがRNAであることが、本開示によって企図される。また、RNA内の配列に位置するタンパク質相互作用部位がナノ粒子に対して近くまたは遠くになるように、ポリヌクレオチドがナノ粒子に付着されることも企図される。これらの態様では、「近く」および「遠く」は、ポリヌクレオチド上の中間点を指す。例えば、ナノ粒子に付着するポリヌクレオチドの長さが20塩基であれば、その中間点は、ナノ粒子から10塩基の位置になり、タンパク質相互作用部位は、この第10塩基に対して近くまたは遠くであり得る。
ある種の態様では、オリゴヌクレオチドがスペーサーを介してナノ粒子に付着するものを含めた、機能化されたナノ粒子が企図される。本明細書で使用する場合、「スペーサー」は、それ自体は遺伝子発現の調節に関与しないが、ナノ粒子と機能性オリゴヌクレオチドとの間の距離を広げるのに、または多重コピーでナノ粒子に付着する場合には個々のオリゴヌクレオチド間の距離を広げるのに役立つ部分を意味する。したがって、スペーサーは、オリゴヌクレオチドが同一の配列を有するとしても異なる配列を有するとしても、個々のオリゴヌクレオチド間に並べて配置されることが企図される。一態様では、スペーサーは、存在する場合、有機部分である。別の態様では、スペーサーは、これに限定されないが水溶性ポリマーを含めたポリマーや、核酸、ポリペプチド、オリゴ糖、炭水化物、脂質、エチルグリコール、またはこれらの組み合わせである。
本明細書で提供するナノ粒子は、ナノ粒子間および単一ナノ粒子上のポリヌクレオチド鎖間の協同的挙動をもたらすのに、種々の態様において十分であるような、ポリヌクレオチドのナノ粒子表面上での充填密度を有する。別の態様では、ナノ粒子間の協同的挙動によって、ヌクレアーゼ分解に対するポリヌクレオチドの耐性が増大する。さらに別の態様では、細胞によるナノ粒子の取り込みは、ナノ粒子と結合するポリヌクレオチドの密度によって影響される。参照により本明細書にその全体が組み込まれるPCT/US2008/65366に記載の通り、ナノ粒子の表面上のポリヌクレオチドの密度がより高いことは、細胞によるナノ粒子の取り込みの増大と関連する。
本方法に使用を企図されるポリヌクレオチドとしては、任意の手段を介してナノ粒子に結合されるポリヌクレオチドが挙げられる。ポリヌクレオチドをナノ粒子に付着させる手段にかかわらず、種々の態様における付着は、5’連結、3’連結、ある種類の内部連結、またはこれらの付着の任意の組み合わせを介して行われる。
本明細書で使用する場合、用語「ヌクレオチド」またはその複数形は、本明細書で論じる通りの改変された形や、その他当分野で既知のものと同義的である。ある種の例では、当分野では、天然に存在するヌクレオチド、ならびに重合可能なヌクレオチドの改変形態を包含する、用語「核酸塩基」が使用される。したがって、ヌクレオチドまたは核酸塩基は、天然に存在する核酸塩基、すなわちアデニン(A)、グアニン(G)、シトシン(C)、チミン(T)、ウラシル(U)、ならびに天然に存在しない核酸塩基、すなわちキサンチン、ジアミノプリン、8−オキソ−N6−メチルアデニン、7−デアザキサンチン、7−デアザグアニン、N4,N4−エタノシトシン、N’,N’−エタノ−2,6−ジアミノプリン、5−メチルシトシン(mC)、5−(C3〜C6)−アルキニル−シトシン、5−フルオロウラシル、5−ブロモウラシル、プソイドイソシトシン、2−ヒロドキシ−5−メチル−4−トリアゾロピリジン、イソシトシン、イソグアニン、イノシン、ならびに、Bennerら、米国特許第5,432,272号およびSusan M.FreierおよびKarl−Heinz Altmann、1997、「Nucleic Acids Research」、第25巻:4429〜4443頁に記載されている「天然に存在しない」核酸塩基、を意味する。用語「核酸塩基」には、既知のプリン複素環およびピリジン複素環だけでなく、それらの複素環式類似体および互変異性体も含まれる。さらに、天然に存在するおよび天然に存在しない核酸塩基としては、参照により本明細書にそれぞれその全体が組み込まれる、米国特許第3,687,808号(Meriganら)に;「Antisense Research and Application」、S.T.CrookeおよびB.Lebleu編、CRC Press、1993中の、SanghviによるChapter 15に;Englischら、1991、「Angewandte Chemie,International Edition」、30:613〜722(特に622頁および623頁参照)に;また、「the Concise Encyclopedia of Polymer Science and Engineering」、J.I.Kroschwitz編、John Wiley&Sons、1990、858〜859頁、Cook、「Anti−Cancer Drug Design 1991」、6、585〜607に開示されているものも挙げられる。種々の態様では、ポリヌクレオチドは、最も典型的な意味ではヌクレオシド塩基ではないが、ヌクレオシド塩基として機能する、ある種の「万能塩基」を含めて、核酸塩基のように機能することができる複素環式化合物などの化合物を含めた1種または複数の「ヌクレオシド塩基」または「塩基単位」も含む。万能塩基としては、3−ニトロピロール、任意選択で置換されたインドール(例えば、5−ニトロインドール)、および任意選択で置換されたヒポキサンチンが挙げられる。他の望ましい万能塩基としては、当分野で既知の万能塩基を含めた、ピロール誘導体、ジアゾール誘導体、またはトリアゾール誘導体が挙げられる。
本開示は、種々の実施形態において、遺伝子調節に有用である多価RNA−ナノ粒子組成物を提供する。低分子干渉RNAは、標的RNA(一般にメッセンジャーRNA(mRNA))の一部との相補性を有する(すなわちハイブリッド形成できる)二本鎖RNA因子である。こうした相補性は、一般には、100%であるが、所望により、例えば、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約70%、約75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%のように低くすることができる。例えば、21塩基のうちの19塩基を塩基対合させることができる。したがって、本方法において使用されるオリゴヌクレオチドは、特異的にハイブリッド形成可能であるために、所望の標的核酸と100%相補的である必要はないことが理解されるであろう。さらに、オリゴヌクレオチドは、介在または隣接セグメントがハイブリッド形成事象(例えば、ループ構造またはヘアピン構造)に関与しないように、1つまたは複数のセグメントを飛び越えて互いにハイブリッド形成することができる。任意の所与のオリゴヌクレオチド間の相補性(%)は、当分野で既知のBLAST(Basic Local Alignment Search Tools)プログラムおよびPowerBLASTプログラムを使用して、機械的に決定することができる(Altschulら、1990、「J.Mol.Biol.」、215:403〜410;ZhangおよびMadden、1997、「Genome Res.」、7:649〜656)。
ある態様では、本開示は、特定の核酸を標的にする方法を提供する。いかなる種類の核酸も標的にすることができ、本方法は、例えば、遺伝子発現の治療的調節のために使用することができる(例えば、その開示が参照により本明細書に組み込まれるPCT/US2006/022325を参照されたい)。本発明の方法により標的にされる核酸の例としては、遺伝子(例えば、特定の疾患に関連する遺伝子)、ウイルスRNA、またはmRNA、RNA、一本鎖の核酸が挙げられるが、これに限定されない。
ナノ粒子を機能化させるために、ポリヌクレオチド中のヌクレオチド単位の1つまたは複数の糖かつ/または1つまたは複数のヌクレオチド間連結が、「天然に存在しない」基で置き換えられるような、改変されたポリヌクレオチドが企図される。一態様では、この実施形態は、ペプチド核酸(PNA)を企図する。PNA化合物において、ポリヌクレオチドの糖骨格は、アミド含有骨格で置き換えられる。例えば、その開示が参照により本明細書に組み込まれる、米国特許第5,539,082号;第5,714,331号;および第5,719,262号、およびNielsenら、「Science」、1991、254、1497〜1500を参照されたい。
所与の化合物中のすべての位置が一様に改変される必要はなく、実際には、2つ以上の上述の改変が、単一の化合物中に組み込まれても、あるオリゴヌクレオチド内の単一のヌクレオシドに組み込まれてもよい。こうした「キメラ」アンチセンス化合物は、典型的には、本明細書に記述する通りの改変形態を含む少なくとも1つの領域を含有するが、残りのオリゴヌクレオチドは「未改変」のままである。
RNaseを含まないナノ粒子の調製
クエン酸で安定化された金ナノ粒子(13nm)を、発表されている手順[Frens、Nature Physical Science 241:20〜22(1973)]を使用して調製した。合成後、粒子を0.1%ジエチルピロカーボネート(DEPC)で、攪拌しながら12時間処理し、次いで、121℃で60分間オートクレーブした。重要なことに、また、かなり驚いたことに、紫外分光および透過型電子顕微鏡TEM分析(図1)によって測定された通り、このナノ粒子の光学的および物理的特性は、この比較的過酷な処理によって影響を受けない。それに続くリガンド官能化も、この処理によって影響を受けなかった。RNase Alertキット(Ambion)を使用して、これらの溶液のRNase活性を試験しても、対照または未処理粒子(図2)と比較して、検出可能なRNase活性は示されなかった。
RNaseを含まないナノ粒子の改変
RNaseを含まない得られたナノ粒子は、発表されている方法[Demersら、Anal.Chem.72:5535(2000)]を使用する、チオール化オリゴヌクレオチドによるさらなる改変に適用可能であった。この前処理を行わないと、おそらく、RNAベースの表面を覆うリガンドの急速な分解によって、RNAを用いるそれに続く機能化は達成できなかった。27塩基のRNA鎖と、エチレングリコールスペーサーおよびアルキルチオールを末端とする25塩基の相補鎖とからなる二重鎖をハイブリッド形成させ、チオール−金結合を介して化学吸着が可能となるような、RNaseを含まないAu NPに付加した。この研究のために、これらの配列は、ホタルルシフェラーゼ遺伝子を標的とするように設計された。
RNA−ナノ粒子組成物の細胞内取り込み
組成物が細胞に入る能力を、上述の通りに調製した蛍光(シアニン5、Cy5)組成物を使用して、共焦点顕微鏡によって調べた。RNA−Au NPをHeLa細胞の培養物に添加した。細胞をガラスカバーガラス上で生育させ、蛍光標識したRNA二重鎖で機能化されたナノ粒子で処理した。処理の6時間後、このカバーガラスを取り除き、PBSで洗浄し、スライドガラス上に装備した、PBSを満たしたチャンバーに固定した。画像はすべて、63×の拡大率と633nm HeNeレーザー励起源で、走査型共焦点顕微鏡(Zeiss 510 LSM)よって取得した。画像研究によれば、6時間後のHeLa細胞の細胞質中のいたるところに、蛍光が現れる(図4a)。興味深いことに、DNA Au−NPのように、RNA Au−NPは、細胞に入るために形質移入剤を必要としない[Giljohannら,Nano Lett.7:3818(2007)]。実際、分析的フローサイトメトリーによって、細胞集団の99%より多くでRNA−Au NPの取り込みが確認された(図4b)。このフローサイトメトリー実験のために、細胞を、蛍光標識された(Cy5)RNA−ナノ粒子組成物で処理した。形質移入の6時間後に細胞をトリプシン処理して、細胞培養ウェルから細胞を取り出した。フローサイトメトリーは、励起635nmでDakoCytomation CyAnを使用して行った。
RNA−ナノ粒子組成物の活性
RNA−Au NPが細胞によって内部に取り込まれたことが確定したので、次に、RNA−金ナノ粒子組成物の細胞内活性を試験した。このモデル系の標的として、形質移入されたルシフェラーゼプラスミドを使用して、タンパク質ノックダウン研究をHeLa細胞で行った。HeLa細胞(ATCC)を、10%の熱失活したウシ胎仔血清(FBS)を含むEagleの最少基本培地(EMEM)中で生育させ、5%CO2中で37℃で維持した。細胞を96ウェルプレートに播種し、1日生育させて、ホタルルシフェラーゼとウミシイタケ遺伝子の両方を含有するプラスミド(psiCHECK2、Promega)を形質移入した。プラスミド(ウェルあたり0.2μg)を、製造者の勧告に従ってLipofectamine2000(Invitrogen)を使用して加えた。プラスミド導入後(24時間)、培地を、ホタルルシフェラーゼに指向する機能化されたRNA−Au NP(3nMナノ粒子濃度、約100nM RNA二重鎖濃度)を含有する低血清培地に交換した。処理の1日目には、細胞は約70%集密であった。実験の終わりに、処理された細胞の反復実験ウェルを、Guava EasyCyte Mini(Guava Technologies)を使用して、生存率について計数および測定した。インキュベーション後の生存率は、RNA Au NPで処理した細胞については98%を超えていた。
ology International FluoDia T70蛍光プレートリーダー中に配置した。このサンプルを平衡化(10分)させた後、10μLのウシ胎仔血清(FBS、Gemini Bioproducts)を加えて、サンプルを10%の血清濃度にした。蒸発を防止するために、この反応物を40μLの鉱油で覆った。サンプルの蛍光(励起=530nm、発光=570nm)を5分毎に48時間測定した。ベースラインの蛍光は、FBSの代わりに10μL分量のPBSで処理したサンプルから決定した。反応の終点は、時間の関数として観察される蛍光がさらに増加しなくなった時点に決定した。すべてのサンプルを3回測定した。
ナノ粒子表面上のポリヌクレオチドの方向性
ナノ粒子上に固定化されるRNAの方向性は、制御可能である。Dicer酵素に対するRNA基質を固定化する戦略によって、二本鎖への接近の制御が可能になる。様々な固定化化学、モノチオールまたはジチオール、および様々な長さのスペーサー配列を利用して、RNA二本鎖の数およびRNA二本鎖間の距離を変動させることによって、RNA分解の速度を制御することができる。
本発明は以下をも提供する。
(1)ナノ粒子と結合した1つまたは複数のリボ核酸(RNA)ポリヌクレオチドを含むナノ粒子組成物であって、
該RNAポリヌクレオチドが、ポリペプチドの相互作用部位を有し;
該RNAポリヌクレオチドが、二重鎖を形成するのに適した条件下で該二重鎖を形成する配列を有し;
該二重鎖は、該二重鎖の一本鎖内に、該一本鎖と標的ポリヌクレオチドとのハイブリッド形成を適切な条件下で可能にする、該標的ポリヌクレオチド内の配列と十分に相補的な少なくとも1つのドメインを有し、該二重鎖の該ドメインと該標的ポリヌクレオチド内の該配列とのハイブリッド形成によって、ポリペプチドによって認識される基質部位がもたらされ;
該RNAポリヌクレオチドが、該ポリペプチドの相互作用部位および該ナノ粒子に対して方向特異的な様式で該ナノ粒子と結合する;
ナノ粒子組成物。
(2)前記RNAポリヌクレオチドが、前記ナノ粒子と共有結合している、項目1に記載のナノ粒子組成物。
(3)前記RNAポリヌクレオチドが、前記ナノ粒子と共有結合していない、項目1に記載のナノ粒子組成物。
(4)前記ナノ粒子と結合した各RNAポリヌクレオチドが、同一の配列を有する、項目1に記載のナノ粒子組成物。
(5)前記ナノ粒子と結合した少なくとも2つのRNAポリヌクレオチドが、異なる配列を有する、項目1に記載のナノ粒子組成物。
(6)前記二重鎖が、前記RNAポリヌクレオチドによって形成されたヘアピン構造を含む、項目1に記載のナノ粒子組成物。
(7)前記二重鎖を形成するのに適した条件下で前記RNAポリヌクレオチドとのハイブリッド形成を可能にするための、該RNAポリヌクレオチド内の配列と十分に相補的な配列を有する追加のポリヌクレオチドをさらに含む、項目1に記載のナノ粒子組成物。
(8)前記追加のポリヌクレオチドがRNAである、項目7に記載のナノ粒子組成物。
(9)前記追加のポリヌクレオチドがデオキシリボ核酸(DNA)である、項目7に記載のナノ粒子組成物。
(10)前記追加のポリヌクレオチドが前記ナノ粒子と共有結合している、項目7に記載のナノ粒子組成物。
(11)前記追加のポリヌクレオチドが前記ナノ粒子と共有結合していない、項目7に記載のナノ粒子組成物。
(12)前記ポリペプチドの相互作用部位が、前記RNAポリヌクレオチドの中間点に関して、前記ナノ粒子に対して近位に位置する、項目1に記載のナノ粒子組成物。
(13)前記ポリペプチドの相互作用部位が、前記RNAポリヌクレオチドの中間点に関して、前記ナノ粒子に対して遠位に位置する、項目1に記載のナノ粒子組成物。
(14)前記RNAの表面密度が、少なくとも約2pmol/cm2から約1000pmol/cm2である、項目1に記載のナノ粒子組成物。
(15)前記ポリペプチドの相互作用部位が、RNaseH、RNaseD、RNaseL、RNaseIII、Dicer、Argonaute、Argonaute2、およびヒト免疫不全ウイルスのトランス活性化応答RNA結合タンパク質(TRBP)からなる群より選択されるタンパク質と結合する、項目1に記載のナノ粒子組成物。
(16)前記ポリヌクレオチドの前記ドメインの長さが、約10ヌクレオチドである、項目1に記載のナノ粒子組成物。
(17)前記RNAポリヌクレオチドが、前記標的ポリヌクレオチド内の第2の配列と十分に相補的な第2のドメインをさらに含み、該RNAポリヌクレオチドの該第2のドメインと該標的ポリヌクレオチド内の該第2の配列とのハイブリッド形成によって、第2のポリペプチドによって認識される追加の基質部位がもたらされる、項目16に記載のナノ粒子組成物。
(18)前記ポリヌクレオチドの前記第2のドメインの長さが、約10ヌクレオチドである、項目17に記載のナノ粒子組成物。
(19)前記基質部位と前記追加の基質部位が同じである、項目17に記載のナノ粒子組成物。
(20)前記基質部位と前記追加の基質部位が異なる、項目17に記載のナノ粒子組成物。
(21)前記RNAポリヌクレオチドと前記追加のポリヌクレオチドが、ハイブリッド形成できるのに十分な長さにわたって互いに相補的である、項目7に記載のナノ粒子組成物。
(22)前記RNAポリヌクレオチドと前記追加のポリヌクレオチドが、それらの全長にわたって互いに相補的である、項目21に記載のナノ粒子組成物。
(23)前記RNAポリヌクレオチドが、チオール連結を介して前記ナノ粒子と結合体化される、項目1に記載のナノ粒子組成物。
(24)前記RNAポリヌクレオチドの半減期が、ナノ粒子と結合していない同一のRNAポリヌクレオチドの半減期と少なくとも実質的に同じである、項目1に記載のナノ粒子組成物。
(25)前記RNAポリヌクレオチドの半減期が、ナノ粒子と結合していない同一のRNAポリヌクレオチドの半減期よりも約1倍以上、約2倍以上、約3倍以上、約4倍以上、約5倍以上長い、項目1に記載のナノ粒子組成物。
(26)前記RNAポリヌクレオチドの長さが、約5から約100ヌクレオチドである、項目1に記載のナノ粒子組成物。
(27)前記追加のポリヌクレオチドの長さが、約5から約100ヌクレオチドである、項目7に記載のナノ粒子組成物。
(28)金ナノ粒子である項目1に記載のナノ粒子組成物。
(29)銀ナノ粒子である項目1に記載のナノ粒子組成物。
(30)RNAポリヌクレオチドをナノ粒子に結合させる方法であって、チオール化RNAポリヌクレオチド二重鎖と該ナノ粒子との混合物を一連の溶液中で熟成させて、該RNAポリヌクレオチドを該ナノ粒子に結合させるステップを含み、各溶液は、約0.1M NaClを含む第1の溶液から開始して、先の溶液よりも増大した濃度の塩化ナトリウム(NaCl)を含む、方法。
(31)最後の前記熟成ステップの後に、前記混合物を超音波処理するステップをさらに含む、項目30に記載の方法。
(32)前記ナノ粒子を単離するステップをさらに含む、項目30または31に記載の方法。
(33)RNAをナノ粒子に結合させる方法であって、
(a)約0.1M塩化ナトリウム(NaCl)を含む溶液中で、チオール化RNA二重鎖を該ナノ粒子と混合すること;
(b)先の溶液よりも増大した濃度のNaClをそれぞれ含む一連の塩溶液中で、該混合物を熟成させること;
(c)該混合物を超音波処理すること;および
(d)結合体化された該ナノ粒子を精製すること
を含む方法。
(34)前記一連の塩溶液が、約0.1Mから約0.3M NaClの範囲である、項目33に記載の方法。
(35)オリゴ(エチレングリコール)チオール(OEG)を用いて前記ナノ粒子の表面を不動態化することをさらに含む、項目33に記載の方法。
(36)標的ポリヌクレオチドの発現を調節する方法であって、項目1に記載のナノ粒子組成物のドメインと該標的ポリヌクレオチドをハイブリッド形成させて、ポリペプチドのための基質部位を形成させるステップを含む、方法。
(37)ハイブリッド形成によって前記標的ポリヌクレオチドの分解をもたらす、項目36に記載の方法。
(38)前記ポリペプチドが、RNaseH、RNaseD、RNaseL、RNaseIII、Dicer、Argonaute、Argonaute2、およびTRBPからなる群より選択される、項目37に記載の方法。
Claims (23)
- ナノ粒子と結合したリボ核酸(RNA)ポリヌクレオチドを含むナノ粒子組成物であって、
該RNAポリヌクレオチドが、該ナノ粒子と官能化されており、標的ポリヌクレオチドと同一の配列を含み;
該RNAポリヌクレオチドが、追加のポリヌクレオチドとともに二重鎖を形成するのに適した条件下で該二重鎖を形成する配列を有し、該追加のポリヌクレオチドは、該二重鎖を形成するのに適切な条件で該RNAポリヌクレオチドに対するハイブリッド形成を可能にするために該RNAポリヌクレオチドにおける配列に十分に相補的な配列を有し、該二重鎖はポリペプチドの相互作用部位を提供し;
該追加のポリヌクレオチドは、該追加のポリヌクレオチドと標的ポリヌクレオチドとのハイブリッド形成を適切な条件下で可能にする、該標的ポリヌクレオチド内の配列と十分に相補的であり、長さが10〜30ヌクレオチドである少なくとも1つのドメインを有し、該追加のポリヌクレオチドの該ドメインと該標的ポリヌクレオチドとのハイブリッド形成によって、ポリペプチドによって認識される基質部位がもたらされ;
該RNAポリヌクレオチドが、該ポリペプチドの相互作用部位および該ナノ粒子に対して方向特異的な様式で該ナノ粒子と結合し、ここで、該RNAポリヌクレオチドを該ナノ粒子に結合させるために、該ナノ粒子、該RNAポリヌクレオチドまたはその両方が官能化されている;
ナノ粒子組成物。 - 前記RNAポリヌクレオチドが、前記ナノ粒子と共有結合している、請求項1に記載のナノ粒子組成物。
- 前記ナノ粒子は、少なくとも2つのRNAポリヌクレオチドを含み、該ナノ粒子と結合した各RNAポリヌクレオチドが、同一の配列を有する、請求項1に記載のナノ粒子組成物。
- 前記追加のポリヌクレオチドがRNAである、請求項1に記載のナノ粒子組成物。
- 前記追加のポリヌクレオチドがデオキシリボ核酸(DNA)である、請求項1に記載のナノ粒子組成物。
- 前記追加のポリヌクレオチドが前記ナノ粒子と共有結合していない、請求項1に記載のナノ粒子組成物。
- 前記ポリペプチドの相互作用部位が、前記RNAポリヌクレオチドの中間点に関して、前記ナノ粒子に対して遠位に位置する、請求項1に記載のナノ粒子組成物。
- 前記RNAの表面密度が、少なくとも2pmol/cm2である、請求項1に記載のナノ粒子組成物。
- 前記ポリペプチドの相互作用部位が、RNaseH、RNaseD、RNaseL、RNaseIII、Dicer、Argonaute、Argonaute2、およびヒト免疫不全ウイルスのトランス活性化応答RNA結合タンパク質(TRBP)からなる群より選択されるタンパク質と結合する、請求項1に記載のナノ粒子組成物。
- 前記二重鎖の前記ドメインの長さが、10ヌクレオチドである、請求項1に記載のナノ粒子組成物。
- 前記二重鎖が、前記標的ポリヌクレオチド内の第2の配列と十分に相補的であり、長さが10〜30ヌクレオチドである第2のドメインをさらに含み、該二重鎖の該第2のドメインと該標的ポリヌクレオチド内の該第2の配列とのハイブリッド形成によって、第2のポリペプチドによって認識される追加の基質部位がもたらされる、請求項10に記載のナノ粒子組成物。
- 前記ポリヌクレオチドの前記第2のドメインの長さが、10ヌクレオチドである、請求項11に記載のナノ粒子組成物。
- 前記基質部位と前記追加の基質部位が同じである、請求項11に記載のナノ粒子組成物。
- 前記RNAポリヌクレオチドの長さが、5から100ヌクレオチドである、請求項1に記載のナノ粒子組成物。
- 前記追加のポリヌクレオチドの長さが、5から100ヌクレオチドである、請求項1に記載のナノ粒子組成物。
- 金ナノ粒子である請求項1に記載のナノ粒子組成物。
- 標的ポリヌクレオチドの発現を調節するための、請求項1に記載のナノ粒子組成物であって、該ナノ粒子組成物のドメインを該標的ポリヌクレオチドとハイブリッド形成させて、ポリペプチドのための基質部位を形成させることを特徴とする、ナノ粒子組成物。
- 前記ナノ粒子組成物の前記ドメインと前記標的ポリヌクレオチドとのハイブリッド形成によって前記標的ポリヌクレオチドの分解をもたらす、請求項17に記載のナノ粒子組成物。
- 前記ポリペプチドが、RNaseH、RNaseD、RNaseL、RNaseIII、Dicer、Argonaute、Argonaute2、およびTRBPからなる群より選択される、請求項17または18に記載のナノ粒子組成物。
- 前記追加のポリヌクレオチドが、長さが18〜21ヌクレオチドである少なくとも1つのドメインを有する、請求項1に記載のナノ粒子組成物。
- 前記第2のドメインは、長さが18〜21ヌクレオチドである、請求項11に記載のナノ粒子組成物。
- 前記ナノ粒子は、少なくとも2つのRNAポリヌクレオチドを含み、前記少なくとも1つの結合した各RNAポリヌクレオチドが、異なる配列を有する点で少なくとも1つの他の結合したRNAポリヌクレオチドと異なる、請求項1に記載のナノ粒子組成物。
- 異なる位置または基質部位で同じポリヌクレオチドを標的にする、あるいは異なる遺伝子産物をコードする異なるポリヌクレオチドと結合する、請求項22に記載のナノ粒子組成物。
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CN102281872A (zh) | 2011-12-14 |
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AU2016219644A1 (en) | 2016-09-15 |
US10391116B2 (en) | 2019-08-27 |
KR20110089433A (ko) | 2011-08-08 |
CA2744207C (en) | 2019-05-28 |
US9139827B2 (en) | 2015-09-22 |
JP5749172B2 (ja) | 2015-07-15 |
US20150352138A1 (en) | 2015-12-10 |
JP2015126751A (ja) | 2015-07-09 |
JP2017127327A (ja) | 2017-07-27 |
AU2009316286B2 (en) | 2016-05-26 |
US20100136682A1 (en) | 2010-06-03 |
EP2365803A1 (en) | 2011-09-21 |
EP3335705A1 (en) | 2018-06-20 |
US9844562B2 (en) | 2017-12-19 |
EP2365803B1 (en) | 2017-11-01 |
JP2012509674A (ja) | 2012-04-26 |
WO2010060110A1 (en) | 2010-05-27 |
AU2009316286A1 (en) | 2010-05-27 |
DK2365803T3 (en) | 2018-01-22 |
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