JP6641423B2 - ブロックコポリマーおよびその使用 - Google Patents
ブロックコポリマーおよびその使用 Download PDFInfo
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- JP6641423B2 JP6641423B2 JP2018119659A JP2018119659A JP6641423B2 JP 6641423 B2 JP6641423 B2 JP 6641423B2 JP 2018119659 A JP2018119659 A JP 2018119659A JP 2018119659 A JP2018119659 A JP 2018119659A JP 6641423 B2 JP6641423 B2 JP 6641423B2
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Description
本願は、2008年11月25日に出願の米国仮出願第61/117,892号(これは参照により本明細書に組み入れるものとする)の優先権を主張する。
本発明はポリマー化学の分野に関する。
酸化または加水分解に感受性の高い荷電ブロックまたは化学的部分を含有するブロックコポリマーを開発した。本発明者らは、超分子構造(例えば、ミセルまたはベシクル)および医薬組成物、ならびに前記超分子構造および医薬組成物の調製方法における、こうしたブロックコポリマーの使用を記載する。本発明は、細胞への薬剤(例えば核酸)の送達に特に有用である。
本発明は、1つが親水性で1つが疎水性の少なくとも2種のブロックを有する様々なブロックコポリマーを提供する。さらに、ブロックコポリマーは追加のブロックを含んでいてもよいし、加水分解可能な化学的部分で分断されていてもよく、あるいは改変されていてもよい。コポリマーのそれぞれのブロックは、自己組織化および生物学的機能にとって重要である。各ブロックのサイズは、他のブロックとは無関係に、例えば、各ブロックの機能を調整するように決定することができる。それぞれのブロックは、例えば、US 2003/0059906およびWO 2007/008300(これらは参照により本明細書に組み入れるものとする)に記載されているような、当技術分野で公知の方法を使用して合成し、別のブロックに結合させることができる。
親水性ブロック
親水性ブロック(例えば、PEG)は、(i)核酸/正荷電ポリマー複合体の体内における血清タンパク質、細胞および組織との非特異的相互作用を防止し、取りこまれたリガンドを介して特異的相互作用が設計されるようにし、また、(ii)水性環境における複合体の溶解性を高めるために利用することができる。
疎水性ブロックは、本明細書において、疎水性であるあらゆるポリマーを含み得る。好ましい疎水性ブロックはPPSである。骨格中の硫黄原子の代わりに酸素原子を有するPPSの構造相同体であるポリ(プロピレングリコール)(PPG)を使用することもできる。有用なPPS鎖の長さに比べて、より長いPPG鎖が必要とされ得る。一般的に、融解温度またはガラス転移温度の低いポリマーが最も望ましい。それは、この特性が最も効果的なミセル化を促すからである。
特定の実施形態においては、本発明のコポリマーは2種のみのポリマーブロックを有するが、他の化学的部分、例えば、加水分解可能部分、荷電部分または生物学的活性部分が存在していてもよい。他の実施形態では、コポリマーは3種以上のポリマーブロックを含んでいてもよい。こうした追加ブロックは、例えば、(i)静電的相互作用を介して核酸または他の荷電分子を結合させるため、(ii)自己組織化構造が細胞に入るのを促進するため、および/または(iii)他の生物学的機能を果たすために用いることができる。追加ブロックは、荷電分子(例えば核酸)の結合に用いられる場合、荷電分子との可逆性結合を生じるようなサイズにされるのが好ましい。例えば、荷電分子の少なくとも10%、20%、30%、40%、50%、60%、70%、80%、90%または95%までもが、例えば、細胞質ゾル中または核内で、適切な細胞条件下にブロックから解離可能である。さらに、短いブロックは、任意の毒性を低減または除去するために用いることができる。
本発明のコポリマー中のポリマーブロックは改変可能である。こうした改変としては、荷電基(例えばカルボン酸基、硫酸塩、スルホンおよびアミン)、親水基(例えばヒドロキシル)、疎水基(例えばフェニルもしくはメチル)、加水分解可能な基(例えばエステル、アミド、チオエステル、無水物もしくはケタール部分)、または酸化に感受性のある基を加えることが挙げられる。特に、超分子構造中の水性溶液に暴露されるポリマーブロックの部分は、本明細書に記載の通り、in vivoでのより効果的な取り込みが可能なように1種または複数の荷電基を含めるよう改変することができる。またブロックコポリマーは、本明細書に記載し、当技術分野で公知の各種の基で末端封止することができる。
本自己組織化担体は、標的器官における不可逆的蓄積を回避するため、in vivoでのある種の分解を示し得る。ポリスルフィドは、例えば、過酸化水素などの穏やかな酸化剤の作用により、ポリスルホキシドへ、さらにはポリスルホンへまでもの酸化を容易に受けることが知られている。この酸化は、生物学的条件下で、例えば、マクロファージにより細胞外的に、あるいはエンドソームもしくはリソソーム区画への細胞取り込み後、細胞内的に行われ得る。同様の種類の反応は、廃水泡を消泡するため、チオエーテル末端化PEG(パルプおよび紙加工で乳化剤として使用されるもの)の酸化に使用されている(例えば、米国特許第4,618,400号を参照)。
両親媒性ブロックコポリマーは、広範囲の用途において界面活性剤および分散剤として長い間使用されてきた。ブロックの1つとして選択できる溶媒中の組織化構造の形成は、この性質に基づく。
本発明はまた、ベシクルからミセルを作製する方法を特徴とする。これらの実施形態においては、ミセルは、熱力学的にベシクルを形成する傾向にあるブロックコポリマーから形成される。ミセルの加熱時に、これらは自然にベシクルを形成する。溶解された化合物(例えば薬剤)を含む水系懸濁液剤中にミセルが存在する場合、ベシクルの形成方法によって、ベシクル内部で薬剤のカプセル化が起こる。
本発明の超分子構造(例えばベシクル)を脱水し、乾燥製剤に調製することができる。こうした乾燥製剤は、投与時にin vivoで再水和することができ、in vitroでは投与または他の使用前に再水和することができる。好ましくは、乾燥製剤は、5重量%未満の水を含む。乾燥製剤で許容され得る含水量の限界は、標準方法に従って、保存期間の測定により決定することができる。乾燥製剤は、2週間、1か月、6か月または1年以上の間、安定可能である。例えば本明細書に記載の方法によって超分子構造内にカプセル化された薬剤は、再水和時に活性形態に再構成することができる。乾燥組成物は、任意の水性溶液中で、例えば、製薬上許容可能な希釈剤中で再水和することができる。従来の製剤過程では、多数の乾燥方法により、容易に含水量を実質的に5%未満にすることができる。
例えば熱処理によるミセル生成に適する条件において、本発明のブロックコポリマーは、薬剤、例えば、ペプチド、核酸、抗生物質(例えばアンピシリンもしくはテトラサイクリン)、化学療法剤(例えばアドリアマイシン)または他の小分子薬剤のカプセル化に使用することができる。ラメラ相が形成されることになっている場合、ベシクルはラメラ構造曲変形から生成することができる。このようにして、水に溶解した薬剤は、ベシクルの内部空洞に封入することができる。また医薬組成物は、親水性、疎水性または両親媒性の薬剤に対する1種または複数のブロックコポリマーのカプセル化効率を高める添加剤を使用してもよい。添加剤は、薬剤とブロックコポリマー中の1種または複数のブロックとの適合性を、例えば、薬剤とブロックコポリマーの1種または複数のブロックとの間の反発力を低減させるか、引力を増強させることにより高めることができる。
本発明の特定の実施形態では、ブロックコポリマー組成物は核酸を含有する。核酸はコポリマーの1種または複数のブロックと結合可能であり、また、ブロックコポリマーを含有する超分子構造(例えばミセル、ベシクル)へ組み入れることができる。好ましい実施形態においては、核酸は、1種または複数のブロックコポリマーを含有する医薬組成物中に治療上有効な量で存在する。例としては、アンチセンスオリゴヌクレオチド、短鎖干渉RNAs (small interfering RNAs)、アプタマーおよびプラスミドDNAがある。
ポリペプチドは本発明の実施形態で用いることができる。ポリペプチドのアミノ酸は、天然、非自然またはそれらの混合物であってもよい。ポリペプチドは、当技術分野で公知の方法を使用し、組換え遺伝子工学手法または化学合成法により得ることができる。ポリペプチドの具体例は、単鎖ペプチド断片(例えば、従来のペプチド結合により連結されている5〜20個のアミノ酸のポリペプチド)、天然型タンパク質、および抗体またはそれらの抗原結合性フラグメントである。
コポリマーは、送達および治療作用の両方に関する生物学的経路を利用することができる。一実施形態において、水性環境においてナノスケールミセルまたはベシクルに自己組織化するブロックコポリマーは、siRNAまたは他の核酸などの薬剤の送達に利用することができる。さらに、本発明のブロックコポリマーは、薬剤の効率的送達のために、変化する細胞内環境、例えば、エンドソームの還元的環境、および治療作用のための生物学的経路、例えば、遺伝子サイレンシングのためのRNAi経路の活性化を利用することができる。初期エンドソーム内で治療剤の放出を誘導し、それを不安定にし得る生物学的応答性物質の開発は、現在の送達系の限界を克服することができる送達系の開発として見込みがある。
本発明のブロックコポリマーは、遺伝子を上方または下方制御するための核酸を送達するのに用いることができる。核酸の例としては、siRNA、ODN(アンチセンス)、および治療用タンパク質をコードするpDNAを含むpDNAが挙げられる。
本発明は、本発明の医薬組成物を細胞と接触させること、または動物に投与することにより、細胞または動物(例えば哺乳動物)または植物に薬剤(例えば核酸)を送達する方法を提供する。送達は、細胞(例えば、真核細胞、植物細胞、動物細胞、無脊椎動物細胞、哺乳動物もしくはヒト細胞などの脊椎動物細胞、または病原体細胞)において標的遺伝子の発現を低下または阻害し得るか、あるいは、医薬組成物に含有されている薬剤に特異的な任意の機序によって動物または細胞を治療することができる。方法は、病原体による感染症の処置に、または非病原性疾患、例えば、癌、術後癒着、瘢痕形成、もしくは(例えば、バルーン血管形成またはステントグラフト留置術による)動脈閉塞の除去後の再狭窄の処置に用いることができる。典型的には、細胞において内部移行した核酸は、標的遺伝子、例えば、疾患に関連したもの(例えば、遺伝子の全部またはある領域、遺伝子プロモーター、または遺伝子およびそのプロモーターの一部)の発現を特異的に低下または阻害する。具体的な病原体としては、細菌、原生動物、酵母、および真菌が挙げられる。いくつかの態様において、核酸または他の分子は、脊椎動物細胞もしくは病原体細胞(例えば、細菌細胞、酵母細胞、または真菌細胞)において内因性遺伝子の発現を阻害するか、あるいは病原体に感染した細胞(例えば、植物細胞または動物細胞)において病原体遺伝子の発現を阻害する。また核酸または他の分子は、例えば、癌細胞または望ましくない効果(例えば、再狭窄、瘢痕形成、および術後癒着)を生じる細胞において、内因性遺伝子の発現を低下または阻害することもできる。いくつかの態様において、標的遺伝子は、発癌遺伝子などの癌に関連した遺伝子、または突然変異体タンパク質、ドミナントネガティブタンパク質、もしくは過剰発現したタンパク質などの疾患関連タンパク質をコードする遺伝子である。
本発明の組成物は、動物(例えばヒト)における疾患(例えば癌)の治療に使用することができる。本明細書に記載の方法を用いて治療することができる具体的な癌としては、前立腺癌、乳癌、卵巣癌、膵臓癌、胃癌、膀胱癌、唾液腺癌、消化管癌、肺癌、結腸癌、黒色腫、脳腫瘍、白血病、リンパ腫、および癌腫が挙げられる。また良性腫瘍も本発明の方法を用いて治療または予防することができる。標的とすることができる他の癌および癌関連遺伝子は当技術分野において公知である。
PDI = μ2/(Γ)2
式中、μ2は第2キュムラントであり、Γは崩壊速度である。この場合、崩壊速度は、試料中で確認された崩壊速度に関するガウス分布の典型である。
PEG-PPSナノ粒子が胃内pHなどの厳しい条件に耐えることができることを鑑み、本発明者らは、腸リンパ管におけるそれらの輸送を検討し、腸内の脂肪取り込みと関連のある機序により処理されるそれらの可能性を測定した。これは、caco-2細胞(腸細胞)およびリンパ内皮細胞(LEC)の共培養モデルを使用して測定し、取り込み、パッケージングおよび移送(総称して輸送と称する)について十分に特性決定した。PPSベースのナノ粒子の表面特性を処理し、効果的輸送を提供することができることが測定された。例えば、約10%の末端鎖基がカルボキシル官能基で置換された粒子は、表面電荷を欠いている同等の粒子に比べると、5倍以上の高いレベルで輸送されていた。他の表面帯電部分、例えば硫酸塩およびスルホンなどは、最適化後に同様に効果的である。
本発明の特定の実施形態の記載は、例示目的で示している。網羅的であることを意図するものではなく、本発明の範囲を本明細書に記載の特定形態に限定することを意図するものでもない。本発明はいくつかの実施形態に関して記載されているが、特許請求の範囲に示した本発明の趣旨および範囲から逸脱することなく、様々な変更を行うことができることは、当業者により理解されよう。本明細書で参照した全ての特許、特許出願および刊行物は、参照により本明細書に組み入れるものとする。
本発明は、以下の実施形態を包含する。
(実施形態1)
親水性ブロックおよび疎水性ブロックを含むブロックコポリマーであって、前記親水性または疎水性ブロックが加水分解可能な化学的部分で分断されている前記ブロックポリマー。
(実施形態2)
前記親水性ブロックが500〜10,000 Daの分子量を有する、実施形態1に記載のブロックコポリマー。
(実施形態3)
前記疎水性ブロックが300〜5,000 Daの分子量を有する、実施形態1に記載のブロックコポリマー。
(実施形態4)
前記ブロックコポリマーが超分子構造へ自己組織化することができる、実施形態1〜3のいずれか1項に記載のブロックコポリマー。
(実施形態5)
前記超分子構造がミセルまたはベシクルである、実施形態4に記載のブロックコポリマー。
(実施形態6)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態1〜5のいずれか1項に記載のブロックコポリマー。
(実施形態7)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)、またはポリペプチドを含む、実施形態1〜6のいずれか1項に記載のブロックコポリマー。
(実施形態8)
前記親水性ブロックがPEGを含み、前記疎水性ブロックがPPSを含む、実施形態1〜7のいずれか1項に記載のブロックコポリマー。
(実施形態9)
前記の加水分解可能な化学的部分がエステル、アミド、チオエステル、無水物またはケタールである、実施形態1〜8のいずれか1項に記載のブロックコポリマー。
(実施形態10)
実施形態1〜9のいずれか1項に記載のブロックコポリマーと製薬上許容可能な希釈剤とを含む医薬組成物。
(実施形態11)
親水性ブロックおよび疎水性ブロックを含むブロックコポリマーと添加剤とを含む超分子構造。
(実施形態12)
前記構造がミセルまたはベシクルである、実施形態11に記載の超分子構造。
(実施形態13)
さらに薬剤を含む、実施形態11または12に記載の超分子構造。
(実施形態14)
前記薬剤が疎水性である、実施形態13に記載の超分子構造。
(実施形態15)
前記疎水性薬剤がデキサメタゾン、パクリタキセル、シクロスポリンA、シロリムス、エベロリムス、タクロリムス、アンフォテリシンBまたはアドリアマイシンから選択される、実施形態14に記載の超分子構造。
(実施形態16)
前記薬剤が親水性である、実施形態13に記載の超分子構造。
(実施形態17)
前記親水性薬剤がポリペプチドまたは核酸である、実施形態16に記載の超分子構造。
(実施形態18)
前記ポリペプチドが抗体またはその抗原結合性フラグメントである、実施形態17に記載の超分子構造。
(実施形態19)
前記親水性薬剤が抗生物質または化学療法剤である、実施形態16に記載の超分子構造。
(実施形態20)
前記薬剤が5%を超える効率でカプセル化される、実施形態13に記載の超分子構造。
(実施形態21)
前記薬剤が50%を超える効率でカプセル化される、実施形態13に記載の超分子構造。
(実施形態22)
前記薬剤が90%を超える効率でカプセル化される、実施形態13に記載の超分子構造。
(実施形態23)
前記添加剤が1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エンおよびポリ(エチレングリコール)から選択される、実施形態11〜22のいずれか1項に記載の超分子構造。
(実施形態24)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態11〜23のいずれか1項に記載の超分子構造。
(実施形態25)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)またはポリペプチドを含む、実施形態11〜24のいずれか1項に記載の超分子構造。
(実施形態26)
前記親水性ブロックがPEGであり、前記疎水性のブロックがPPSである、実施形態11〜25のいずれか1項に記載の超分子構造。
(実施形態27)
実施形態13〜23のいずれか1項に記載の超分子構造と製薬上許容可能な希釈剤とを含む医薬組成物。
(実施形態28)
超分子構造がベシクルである、実施形態27に記載の医薬組成物。
(実施形態29)
超分子構造がミセルである、実施形態27に記載の医薬組成物。
(実施形態30)
超分子構造に薬剤をカプセル化する方法であって、
a. (i) 親水性ブロックおよび疎水性ブロックを含むブロックコポリマー、(ii)添加剤、ならびに(iii)薬剤、の混合物に、前記混合物を均質化するのに十分な量の熱を加えるステップと、
b. 水性溶液中で前記混合物を希釈するステップ
とを含む方法。
(実施形態31)
前記超分子構造がミセルである、実施形態30に記載の方法。
(実施形態32)
前記超分子構造がベシクルである、実施形態30に記載の方法。
(実施形態33)
前記添加剤がDBUまたはPEGである、実施形態30〜32のいずれか1項に記載の方法。
(実施形態34)
ベシクルの製造方法であって、
a. 親水性ブロックおよび疎水性のブロックを含むブロックコポリマーからミセルを形成させるステップであって、前記ブロックコポリマーのベシクルがミセルよりも熱力学的に安定しているステップと;
b. 前記ミセルに熱を加え、前記ベシクルを形成させるステップ
とを含む方法。
(実施形態35)
前記ベシクルが70〜800nmのサイズを有する、実施形態34に記載の方法。
(実施形態36)
前記ミセルが、ステップ(b)で前記ベシクルへカプセル化されている薬剤を含む溶液中に懸濁される、実施形態34または35に記載の方法。
(実施形態37)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態34〜36のいずれか1項に記載の方法。
(実施形態38)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)またはポリペプチドを含む、実施形態34〜37のいずれか1項に記載の方法。
(実施形態39)
前記親水性ブロックがPEGであり、前記疎水性ブロックがPPSである、実施形態34〜38のいずれか1項に記載の方法。
(実施形態40)
実施形態34〜39のいずれか1項に記載の方法により製造されるベシクル。
(実施形態41)
親水性ブロックおよび疎水性ブロックを含むブロックコポリマーを含んでなるミセルを含む乾燥製剤であって、5重量%未満の水を含む前記製剤。
(実施形態42)
前記製剤が2重量%未満の水を含む、実施形態41に記載の製剤。
(実施形態43)
前記ミセル中にカプセル化された薬剤をさらに含む、実施形態41または42に記載の製剤。
(実施形態44)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態41〜43のいずれか1項に記載の製剤。
(実施形態45)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)、またはポリペプチドを含む、実施形態41〜44のいずれか1項に記載の製剤。
(実施形態46)
前記親水性ブロックがPEGであり、前記疎水性ブロックがPPSである、実施形態41〜45のいずれか1項に記載の製剤。
(実施形態47)
(i) 正荷電ブロックを含むブロックコポリマーと、(ii) 核酸と、を含む超分子構造であって、60nm以下の最大直径を有する前記超分子構造。
(実施形態48)
前記超分子構造が分子またはベシクルである、実施形態47に記載の超分子構造。
(実施形態49)
前記ブロックコポリマーが親水性ブロックまたは疎水性ブロックをさらに含む、実施形態47または48に記載の超分子構造。
(実施形態50)
前記ブロックコポリマーが親水性ブロックおよび疎水性ブロックをさらに含む、実施形態49に記載の超分子構造。
(実施形態51)
前記の最大直径が40nm以下である、実施形態47〜50のいずれか1項に記載の超分子構造。
(実施形態52)
前記ブロックコポリマーがPEG-PPS-PEIを含む、実施形態47〜51のいずれか1項に記載の超分子構造。
(実施形態53)
前記核酸が一本鎖オリゴヌクレオチド、短鎖干渉RNA(short interfering RNA)、アプタマーまたはプラスミドDNAを含む、実施形態47〜52のいずれか1項に記載の超分子構造。
(実施形態54)
細胞を実施形態47〜53のいずれか1項に記載の超分子構造と接触させることを含む、核酸を用いた細胞のトランスフェクト方法。
(実施形態55)
PEG-PPS-PEIを含むブロックコポリマー。
(実施形態56)
PPSブロックおよびPEIブロックが、エンドソーム中で不安定な結合を介して結合されている、実施形態55に記載のブロックコポリマー。
(実施形態57)
前記結合がジスルフィド結合、ビニルエーテル、オルトエステル、アシルヒドラゾンまたは-N-PO 3 -基を含む、実施形態56に記載のブロックコポリマー。
(実施形態58)
前記PEIに複合体形成されている核酸をさらに含む、実施形態55〜57のいずれか1項に記載のブロックコポリマー。
(実施形態59)
実施形態55〜58のいずれか1項に記載のブロックコポリマーと、製薬上許容可能な希釈剤とを含む医薬組成物。
(実施形態60)
第1および第2のブロックコポリマーを含み、10〜60nmのサイズを有するミセルであって、前記第1および第2のブロックコポリマーがそれぞれ親水性ブロックおよび疎水性ブロックを含む、前記ミセル。
(実施形態61)
前記ミセルが10〜40nmのサイズを有する、実施形態60に記載のミセル。
(実施形態62)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態60または61に記載のミセル。
(実施形態63)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)、またはポリペプチドを含む、実施形態60〜62のいずれか1項に記載のミセル。
(実施形態64)
前記の第1のブロックコポリマーがPEGおよびPPSを含み、前記の第2のブロックコポリマーがPEIおよびPPSを含む、実施形態60〜63のいずれか1項に記載のミセル。
(実施形態65)
親水性ブロックおよび疎水性のブロックを含む第1のブロックコポリマーと、親水性ブロック、疎水性ブロックおよび正荷電ブロックを含む第2のブロックコポリマーとを含むミセル。
(実施形態66)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、およびポリ(N-アクリロイルモルホリン)から独立して選択される部分を含む、実施形態65に記載のミセル。
(実施形態67)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)、およびポリペプチドから独立して選択される部分を含む、実施形態65または66に記載のミセル。
(実施形態68)
前記荷電ブロックがポリペプチド、ポリ(エチレンイミン)、ポリ(アミドアミン)、ポリ(ナトリウム 1-(N-アクリロイルピペラジン-1-イル)ジアゼン-1-イウム-1,2-ジオレート)、ポリ(ナトリウム 1-(N-アクリロイルホモピペラジン-1-イル)ジアゼン-1-イウム-1,2-ジオレート)、またはポリ(ナトリウム 1-(N-アクリロイル-2,5-ジメチルピペラジン-1-イル)ジアゼン-1-イウム-1,2-ジオレート)を含む、実施形態65〜67のいずれか1項に記載のミセル。
(実施形態69)
前記の第1のブロックコポリマーがPEG-PPSであり、前記の第2のブロックコポリマーがPEG-PPS-PEIである、実施形態65〜68のいずれか1項に記載のミセル。
(実施形態70)
前記ミセルが直径20〜50nmである、実施形態65〜69のいずれか1項に記載のミセル。
(実施形態71)
実施形態60〜70のいずれか1項に記載のミセルと、製薬上許容可能な希釈剤とを含む医薬組成物。
(実施形態72)
親水性ブロックおよび疎水性ブロックを含むブロックコポリマーを含んでなる超分子構造であって、前記ブロックコポリマーの5〜25%が前記構造の外表面に配置されている荷電化学的部分を有する、前記超分子構造。
(実施形態73)
前記親水性ブロックがポリ(エチレングリコール)、ポリ(エチレンオキシド)-コ-ポリ(プロピレンオキシド)ジブロックもしくはマルチブロックコポリマー、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(エチレン-コ-ビニルアルコール)、ポリ(N-ビニルピロリドン)、ポリ(アクリル酸)、ポリ(エチルオキサゾリン)、ポリ(アルキルアクリレート)、ポリ(アクリルアミド)、ポリ(N-アルキルアクリルアミド)、ポリペプチド、多糖類、ポリ(N,N-ジアルキルアクリルアミド)、ヒアルロン酸、またはポリ(N-アクリロイルモルホリン)を含む、実施形態72に記載の超分子構造。
(実施形態74)
前記疎水性ブロックがポリ(プロピレンスルフィド)、ポリ(プロピレングリコール)、エステル化ポリ(アクリル酸)、エステル化ポリ(グルタミン酸)、エステル化ポリ(アスパラギン酸)、またはポリペプチドを含む、実施形態72または73に記載の超分子構造。
(実施形態75)
前記親水性ブロックがPEGであり、前記疎水性ブロックがPPSである、実施形態72〜74のいずれか1項に記載の超分子構造。
(実施形態76)
前記の荷電化学的部分がカルボン酸、硫酸塩またはスルホンである、実施形態72〜75のいずれか1項に記載の超分子構造。
(実施形態77)
実施形態72〜76のいずれか1項に記載の超分子構造と、製薬上許容可能な希釈剤とを含む医薬組成物。
(実施形態78)
さらに薬剤を含む、実施形態10、27、59または77に記載の医薬組成物。
Claims (9)
- (i) ポリ(プロピレンスルフィド)(PPS)ブロック及び正荷電ブロックを含むブロックコポリマーと、(ii) 核酸と、を含む超分子構造体であって、60nm以下の最大直径を有する前記超分子構造体。
- 前記超分子構造体がミセルまたはベシクルである、請求項1に記載の超分子構造体。
- 前記ブロックコポリマーが親水性ブロックをさらに含む、請求項1または2に記載の超分子構造体。
- 前記の最大直径が40nm以下である、請求項1〜3のいずれか1項に記載の超分子構造体。
- 前記正電荷ブロックがポリエチレンイミン(PEI)である、請求項1〜4のいずれか1項に記載の超分子構造体。
- 前記ブロックコポリマーがPEG-PPS-PEIを含む、請求項1〜5のいずれか1項に記載の超分子構造体。
- 前記超分子構造体がPEG-PPSをさらに含む、請求項1〜6のいずれか1項に記載の超分子構造体。
- 前記核酸が一本鎖オリゴヌクレオチド、短鎖干渉RNA(short interfering RNA)、アプタマーまたはプラスミドDNAを含む、請求項1〜7のいずれか1項に記載の超分子構造体。
- 細胞を前記核酸でトランスフェクトするために使用される、請求項1〜8のいずれか1項に記載の超分子構造体。
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EP2356228A1 (en) | 2011-08-17 |
JP5814793B2 (ja) | 2015-11-17 |
EP2356228B1 (en) | 2023-05-03 |
JP2020073678A (ja) | 2020-05-14 |
JP2015071762A (ja) | 2015-04-16 |
JP2018188642A (ja) | 2018-11-29 |
US10335499B2 (en) | 2019-07-02 |
JP6409020B2 (ja) | 2018-10-17 |
US20160256569A1 (en) | 2016-09-08 |
US20110223217A1 (en) | 2011-09-15 |
WO2010068432A1 (en) | 2010-06-17 |
US9271929B2 (en) | 2016-03-01 |
JP5995939B2 (ja) | 2016-09-21 |
JP2017002280A (ja) | 2017-01-05 |
JP2012509983A (ja) | 2012-04-26 |
US20200000936A1 (en) | 2020-01-02 |
EP2356228A4 (en) | 2015-05-13 |
US20220168448A1 (en) | 2022-06-02 |
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