JP2015520126A - ビス−ポリマー脂質−ペプチド複合体及びそのナノ粒子 - Google Patents
ビス−ポリマー脂質−ペプチド複合体及びそのナノ粒子 Download PDFInfo
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- JP2015520126A JP2015520126A JP2015505867A JP2015505867A JP2015520126A JP 2015520126 A JP2015520126 A JP 2015520126A JP 2015505867 A JP2015505867 A JP 2015505867A JP 2015505867 A JP2015505867 A JP 2015505867A JP 2015520126 A JP2015520126 A JP 2015520126A
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Abstract
Description
本願は、2012年4月10日に出願された米国特許仮出願第61/622,330号、及び2012年7月6日に出願された米国特許仮出願第61/668,923号に対する優先権を主張し、それらの出願の全体は、参照によりそれらの全体において組み込まれている。
本願は、米国国防総省の陸軍局により与えられた認可番号第W91NF−09−1−0374号、米国エネルギー省の科学局、基礎エネルギー科学局により与えられた認可番号第DE−AC02−05CH11231号下で、政府支援により成された。政府は、本発明において一定の権利を有する。
I.概要
本発明は、in vivoでの薬物及び他の積荷の送達のためのミセルナノキャリアを提供する。ナノ粒子は、標的化または非標的化され得る。本発明のナノキャリアにより送達され得る適切な積荷は、これらに限定されないが、ワクチン、DNAまたはRNA等の核酸、ペプチド、タンパク質、造影剤、及び薬物を含む。さらに本発明のナノ粒子は、遺伝子治療、発現された核酸、または発現可能な核酸の対象への投与に有用である。
「複合体(conjugate)」とは、第一のポリマー、第二のポリマー、ペプチド、及び疎水性部分を全て一緒に結合して有する化合物について言及する。複合体は、自己結合して、らせん束を形成することを可能にする。らせん束は、2〜6個、典型的に3または4個の複合体を含む。
1)アラニン(A)、グリシン(G);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リシン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(V)、トリプトファン(W);
7)セリン(S)、トレオニン(T);及び
8)システイン(C)、メチオニン(M)
(例えば、Creighton, Proteins (1984)を参照)。
いくつかの実施態様では、本発明は、約10〜約100個のアミノ酸を有する第一のペプチドを有する複合体を提供し、ここでのペプチドは、らせん構造を用いる。さらに複合体は:N−末端及びC−末端残基以外のペプチドのアミノ酸残基に共有結合した第一のポリマー;ペプチドのC−末端アミノ酸残基に共有結合した少なくとも1つの第二のポリマー;並びにペプチドのN−末端に共有結合した疎水性部分を含み、ここでの疎水性部分は、第三のポリマーまたは脂質部分を含む。
本発明のナノ粒子は、当業者に公知の任意の適切な方法により調製され得る。例えばナノ粒子は、最初に適切な溶媒中に約1nM〜約1M、または約1μM〜約100mM、または約1mM〜約100mMの任意の濃度で複合体を溶かすことにより調製され得る。或いは、複合体は、溶液の約0.1〜約50重量%、または約1〜約50重量%、または約1〜約25重量%の濃度で溶解され得る。複合体は、自己集合して本発明のらせん束形成する。その後にらせん束は、自己集合して粒子を形成する。いくつかの実施態様では、本発明は、複合体を本発明の粒子に自己集合させるのに十分な条件下で、本発明の複数の複合体を維持することにより、本発明の粒子を形成する方法を提供する。いくつかの実施態様では、複合体は、約1nM〜約1Mの濃度である。いくつかの実施態様では、複合体は、約1μM〜約1Mの濃度である。いくつかの実施態様では、複合体は、約1μM〜約1100mMの濃度である。いくつかの実施態様では、複合体は、約1μM〜約1mMの濃度である。
いくつかの実施態様では、本発明は、対象に粒子を投与することを含んで成る、対象に診断用または治療用薬剤を送達するための方法を提供する。いくつかの実施態様では、粒子は、診断用または治療用薬剤をカプセル封入する。他の実施態様では、診断用または治療用薬剤は、本発明の粒子に共役または結合する。したがって、粒子は、約20〜約200個の本発明の複合体、及び送達される診断用または治療用薬剤を含む。いくつかの実施態様では、治療用薬剤は、ドキソルビシン、テモゾロマイド及びラパマイシンから成る群から選定される。
一般に本発明の標的作用剤は、器官、組織、細胞、細胞外マトリクス、または細胞内領域と関連付けられる標的等の、注目の任意の標的と関連付けられ得る。特定の実施態様では、標的は、がん症状等の特定の病状と関連付けられ得る。いくつかの実施態様では、標的成分は、受容体等の1つの標的のみに特異的であり得る。適切な標的は、これらに限定されないが、DNA、RNA等の核酸、または修飾されたその誘導体を含み得る。さらに適切な標的は、これらに限定されないが、細胞外タンパク質等のタンパク質、受容体、細胞表面受容体、腫瘍マーカー、膜貫通タンパク質、酵素、または抗体を含み得る。適切な標的は、例えば細胞の表面上に存在し得る単糖、二糖、または多糖等の炭水化物を含み得る。
本発明において使用される治療用薬剤または作用剤は、対象における症状の処置に向けた任意の作用剤を含み得る。一般に当業界において公知である任意の治療用薬剤は、米国薬局方(U.S.P)、Goodman及びGilmanのThe Pharmacological Basis of Therapeutics, 第10編、McGraw Hill, 2001; Katzung編、Basic and Clinical Pharmacology, McGraw-Hill/Appleton & Lange,第8編、September 21, 2000;Physician’s Desk Reference (Thomson Publishing; 及び/またはThe Merck Manual of Diagnosis and Therapy, 第18編、2006, Beers及びBerkow編、Merck Publishing Group;或いは動物モデルでは、The Merck Veterinary Manual、第9編、Kahn編, Merck Publishing Group, 2005に挙げられた作用剤を限定なく含めて使用されてよく;その全ては、参照により本明細書中に含まれる。
本発明において用いられる診断用薬剤は、例えば以下の参照において提供されるような、当業界において公知の任意の診断用薬剤を含み得る:Armstrong等、Diagnostic Imaging、第5編、Blackwell Publishing(2004);Torchilin,V.P.編、Targeted Delivery ofImaging Agents、CRC Press(1995);Vallabhajosula, S., Molecular Imaging: Radiopharmaceuticals for PET and SPECT, Springer(2009)。診断用薬剤は、多様な方法により、これらに限定されないが、γ線放射、放射活性、音波発生、光学、蛍光、吸収、磁気または断層撮影法シグナルを含む検出可能なシグナルを提供及び/または増強する作用剤として含まれることにより検出され得る。診断用薬剤を画像化するための技術は、これらに限定されないが、単光子放出コンピューター断層撮影法(SPECT)、磁気共鳴映像法(MRI)、光学画像化、ポジトロン放出断層撮影法(PET)、コンピューター断層撮影法(CT)、X線画像化、γ線画像化等を含み得る。
さらに本発明のナノ粒子は、任意の発現または発現可能な核酸配列を、遺伝子治療または酢酸ワクチン接種のための細胞に送達するために使用され得る。細胞は、送達の間にin vivoまたはin vitroにあり得る。核酸は、デオキシリボ核酸(DNA)またはリボ核酸(RNA)等の任意の適切な核酸であり得る。さらに任意の適切な細胞は、核酸の送達に使用され得る。
ナノキャリアが投与され、上記の積荷を送達する場合、ナノキャリアは、任意の適切な担体、すなわち生理学的に許容され得る担体と共に、任意の適切な組成物中にあり得る。本明細書において使用される用語「キャリア」は、典型的に治療用薬剤等の薬物の希釈剤または賦形剤として使用される不活性物質について言及する。さらに用語は、典型的に組成物に粘着性を与える不活性物質を包含する。典型的に生理学的に許容される得る担体は、液体で存在する。液体の担体の例は、生理食塩水、リン酸緩衝液、標準緩衝食塩水、水、緩衝水、塩類、グリシン、高められた安定性を提供する糖タンパク質(例えばアルブミン、リポタンパク質、グロブリン)等を含む。生理学的に許容され得る担体は、投与される特定の組成物により、及び組成物を投与するために用いられる特定の方法によりある程度決まるので、本発明の医薬組成物には、多種多様な製剤が存在する(例えばRemington’s Pharmaceutical Sciences、第17編、1989を参照)。
診断用及び治療用薬剤の充填は、例えば以下の参照において開示されるような当業界において公知の多様な方法により実施され得る:de Villiers, M. M.等編, Nanotechnology in Drug Delivery, Springer (2009);Gregoriadis, G.編, Liposome Technology: Entrapment of drugs and other materials into liposomes, CRC Press (2006)。いくつかの実施態様では、1つ以上の治療用薬剤は、ナノキャリア中に充填され得る。ナノキャリアの充填は、例えば能動的または受動的な方法において実施され得る。例えば治療用薬剤がナノキャリア中にカプセル封入されるように、治療用薬剤は、ナノキャリアの自己集合工程の間に、溶液中に含められ得る。さらに特定の態様では、治療用薬剤は、ラメラ層中に埋め込まれ得る。他の態様では、治療用薬剤は、ナノキャリア中に能動的に充填され得る。例えばナノキャリアは、エレクトロポレーション等の条件にさらされてよく、ここでのラメラ膜は、治療用薬剤を含む溶液に浸透できるようにされることにより、治療用薬剤をリポソームの内部体積中に侵入できるようにする。
いくつかの態様では、本発明は、疾患を伴う対象を処置するための方法を提供する。方法は、治療有効量の粒子を対象に投与することを含む。粒子は、本発明の約20〜約200個の複合体、及び治療用薬剤を含む。これにより疾患は処置される。
実施例1:ビス−ポリマー脂質−ペプチド複合体の合成
材料:Fmoc−保護アミノ酸、2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェイト(HBTU)、2−(6−クロロ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルアミニウムヘキサフルオロホスフェイト(HCTU)は、EMDバイオサイエンスから購入し、そしてさらなる精製をせずに使用した。Fmoc−保護アミノ酸の側鎖保護基は、以下の通りであった:Lys(Boc)、Glu(OtBu)、Asp(OtBu)、Cys(Trt)、Arg(Pbf)、His(Trt)、Trp(Boc)、Gln(Trt)、Lys(Alloc)。さらにステアリン酸とペプチドとの複合体のために、Fmoc−Lys(Fmoc)−OHを使用し、そしてリンカー、Fmoc−6−Ahx−OH(Sigma Aldrich)を、ペプチドとアルキル尾部の間に付加した。ペプチド合成等級ジエチルプロピルアミン(DIPEA)、トリフルオロ酢酸(TFA)、トリイソプロピルシラン(TIS)、ジエチルエーテル、HPLC等級有機溶媒ジメチルホルムアミド(DMF)、ジクロロメタン(DCM)、アセトニトリル及びイソプロパノールは、Fisherから購入し、そしてさらなる精製をせずに使用した。ピペリジン、ステアリン酸及びドキソルビシンは、Sigma Aldrichから購入した。PEG(2000)−マレイミド及びPEG(750)−COOHエステルは、Rapp Polymereから購入した。陰性染色試薬リンタングステン酸は、Ted Pellaから購入し、そしてDI水中の2重量%のストック溶液として調製した。
ネガティブ染色化透過電子顕微鏡法。凍結乾燥ペプチド粉体を、0.1mg/mLで、25mMのリン酸緩衝液中に、pH7.4で溶かした。5μLのペプチド溶液を、放電した穴のある炭素被覆グリッド(Ted Pella 01824)上に滴下した。過剰なペプチド溶液を除去した後に、5μLのリンタングステン酸(2重量%、pH=3.3)溶液を2分間適用した。サンプルを空気中で乾燥させ、そしてFEI Tecnai 12透過型電子顕微鏡を用いて、120kVで試験した。
6-p-(4-(N-マレイミドメチル)シクロヘキサン-1-アミノ)ベンジル 1,4,8,11−テトラアザシクロテトラデカン−N,N’,N”,N’’’テトラアセテート(6-BAT-マレイミド)の合成。6-p-アミノベンジル 1,4,8,11-テトラアザシクロテトラデカン−N,N’,N”,N’’’テトラアセテート(6−アミノベンジル TETA、25mg)を、リン酸緩衝化生理食塩水(PBS 1×、8mL)中で、スルホ−SMCC(25mg、ProteoChem、Denver)と反応させ、そして1Mの水酸化ナトリウム溶液を添加し、2時間、pHを7で維持した。反応混合物を、0.1%のTFA溶液(4mL)で希釈した。逆相HPLCシステム(Jupiter Proteo C12、250×10mm)により、6-BATマレイミドを単離し、そして220及び254nmの波長で、溶出を観測した。流量は、3mL/分であり、そして5〜60%溶媒Bとして、30分かけて線形勾配を適用した(溶媒A:0.1%TFA DI水(v/v)、溶媒B:0.1%TFAアセトニトリル(v/v))。
ナノキャリアとしてのそれらの潜在能力を検証するために、3−らせんミセルの薬物動力学的評価及び生体内分布を行った。64Cu標識化3−らせんミセルの調製は、金属キレート剤官能化両親媒性ペプチドの通常の両親媒性物質との共集合、その後の64Cuイオンとの高親和性配位反応により達成した。静脈内注入を介して、NDL腫瘍を有するマウスにミセル溶液を投与した。ポジトロン放出断層撮影法(PET)を用いて放射性標識されたミセルの薬物動態を評価し、そして長循環リポソーム及び従来型のDSPE−PEG2Kミセルと比較した。全ての試験させたミセルは、非特異的タンパク質吸着を妨げるように二重のC18尾部及びPEG層から構成されるものと類似する程度の疎水性を有する。図13aは、64Cu−dC18−1coi(PEG2K)−PEG750ミセル投与マウスの薄切りPET画像の冠状(上)及び横切り(下)図を示す。画像は、最大事後確率(MAP)推定によるヒストグラムの再構成後に得た。注入後48時間かけてPET画像を取得し、そして3−らせんミセルが、最小の肝臓及び脾臓蓄積により、血液プール中で高度に濃縮されたままであったことを実証した。図13bは、64Cu−dC18−1coi(PEG2K)−PEG750ミセルの血液放射活性(%ID/cc)を示す。データ曲線は、2相の指数関数的減衰(Y=45.32e-0.0235×t+16.42e-1.27×t、t1/2 α=0.55、β=29.52)と一致した。約15±1.5%ID/gは、注入から48時間後であっても血液プール中で循環したままだった。画像データセットに基づき、3−らせんミセルの薬物動態を、二相モデルを用いて一致させた。ミセルのβ−相血液循環半減期(t1/2,β)を、成功したデンドリマーのものに匹敵する〜29.5時間であると見積もった(図13b)。図13cは、注入から48時間後の血漿及び血液細胞中の算出された%放射活性を示す。%放射活性は、[100×血漿放射活性/(血漿放射活性+血液細胞放射活性)]として算出した。分析は、活性が循環している細胞成分よりもむしろ血漿に限定されたことを示す。
25mMのリン酸緩衝液、pH7.4中に溶解したdC18−1coi(PEG2K)−PEG750の濃度関数として、ピレン蛍光を観測した(図15)。ピレンの濃度は、4×10-7μMで一定のままを保った。両親媒性物質の濃度の増加に伴い、ピレンは、ミセルのコアの中で分割し始めた。曲線の勾配が増加し始めた時の濃度は、臨界ミセル濃度(CMC)を示した。dC18−1coi(PEG2K)−PEG750のCMCは、〜2μMである。
多形性膠芽種(GBM)等の脳腫瘍中への伝達増強送達(GBM)による直接注入により、本発明の薬物充填ミセルを送達する。細胞外の空間を通して注入剤を課す初期バルク流に、注入カテーテルの先端の圧力勾配を使用する。その後に加圧注入剤は、血管周囲の空間に引き込まれ、そして分布は、血管の脈動に大いに助けられる。
薄膜水和法により、混合ミセル(図28)を調製した。50/50重量/重量%のdC18−1coi(P2K)−P750及びDSPE−PEG2000(以下の式Iを参照)を、ガラスバイアル中のメタノールに溶かした。薬物充填混合ミセルのために、薬物(10重量%)を混合物に添加した。真空オーブン中で、3時間かけて溶媒を蒸発させた。乾燥させたフィルムを、25mMのリン酸緩衝液、pH7.4で再水和させ、そして溶液を16時間撹拌し、混合ミセルへの集合を可能にさせた。遠心分離、及びその後のスピン限外ろ過(Amicon遠心分離フィルターユニット、MWカットオフ:3000Da)により、塩及び遊離薬物を除去した。得られた濃縮物を水で洗浄し、そして凍結乾燥させて、混合ミセルを得た。
配列番号1
EVEALEKKVAALECKVQALEKKVEALEHGW
配列番号2
GGGEIWKLHEEFLCKFEELLKLHEERLKKM
配列番号3
AYSSGAPPMPPF
配列番号4
EGKAGEKAGAALKCGVQELEKGAEAGEGGW
配列番号5
EVEALEKKVAALESKVQALEKKVEALEHGW
配列番号6
EVEALEKKVAALECKVQALEKKVEALEHGWGGGK
Claims (31)
- 約10〜約100個のアミノ酸を有する第一のペプチド、ここで、前記ペプチドが、らせん構造をとり;
前記ペプチドのN末端及びC末端アミノ酸残基以外のアミノ酸残基に共有結合した第一のポリマー;
前記ペプチドのC−末端アミノ酸残基に共有結合した少なくとも1つの第二のポリマー;並びに
前記ペプチドのN−末端に共有結合した疎水性部分、ここで、前記疎水性部分が、第三のポリマーまたは脂質部分を含む
を含む、複合体。 - 前記ペプチドが、配列番号1、配列番号2、配列番号4、配列番号5及び配列番号6から成る群から選択される、請求項1に記載の複合体。
- 前記第一のポリマー、及び前記第二のポリマーが、それぞれ親水性ポリマーを含む、請求項1に記載の複合体。
- 前記第一のポリマー及び前記第二のポリマーが、それぞれポリエチレングリコールを含む、請求項1に記載の複合体。
- 前記第一のポリマーの分子量が、約500Da〜約10,000Daである、請求項1に記載の複合体。
- 前記第一のポリマーの分子量が、約1000Da〜約5000Daである、請求項5に記載の複合体。
- 前記第一のポリマーの分子量が、約2000Daである、請求項6に記載の複合体。
- 前記第二のポリマーの分子量が、約250Da〜約5000Daである、請求項1に記載の複合体。
- 前記第二のポリマーの分子量が、約500Da〜約2000Daである、請求項8に記載の複合体。
- 前記第二のポリマーの分子量が、約750Daである、請求項9に記載の複合体。
- 前記第三のポリマーが、ポリブタジエンを含む、請求項1に記載の複合体。
- 前記脂質部分が、1〜6個のC10~20アシル基を含む、請求項1に記載の複合体。
- 前記脂質部分が、1,2または4個のC10~20アシル基を含む、請求項1に記載の複合体。
- 前記ペプチドのC−末端に共有結合した第二のペプチドをさらに含む、請求項1に記載の複合体。
- 前記第二のペプチドが、GGG、HHH、KK、EE、RGD及びAYSSGAPPMPPFから成る群から選択される構成要素を含む、請求項14に記載の複合体。
- 前記第一のペプチドが、配列番号1を含み;
前記第一のポリマーが、約2000Daの分子量を有するポリエチレングリコールを含み;
前記第二のポリマーが、前記ペプチドのC−末端残基に結合し、そして約750Daの分子量を有するポリエチレングリコールを含み;及び
前記疎水性部分が、リシン及び2つのC18アシル鎖を含む脂質部分を含む、請求項1に記載の複合体。 - 2〜6個の請求項1に記載の複合体を含む、らせん束。
- 3個の複合体を含む、請求項17に記載のらせん束。
- 4個の複合体を含む、請求項17に記載のらせん束。
- 約20〜約200個の請求項1に記載の複合体を含む、粒子。
- 治療用薬剤、診断用薬剤、DNA、及びオリゴヌクレオチドから成る群からそれぞれ独立して選択される、少なくとも1つの追加の作用剤をさらに含む、請求項20に記載の粒子。
- 追加の作用剤が、蛍光色素分子、放射性核種、アントラサイクリン、タキサン、及びマクロライドから成る群からそれぞれ独立して選択される、請求項21に記載の粒子。
- 追加の作用剤が、ドキソルビシン、パクリタキセル、及びラパマイシンから成る群からそれぞれ独立して選択される、請求項22に記載の粒子。
- PEG化脂質をさらに含む、請求項20に記載の粒子。
- 前記PEG化脂質が、DSPE−PEG2000を含む、請求項24に記載の粒子。
- 配列番号1を含む、第一のペプチド;
約2000Daの分子量を有するポリエチレングリコールを含む、第一のポリマー;
前記ペプチドのC−末端残基に共有結合し、そして約750Daの分子量を有するポリエチレングリコールを含む、第二のポリマー;並びに
リシン及び2つのC18アシル鎖を含む脂質部分を含む、疎水性部分;並びに
ドキソルビシン、パクリタキセル、及びラパマイシンから成る群から選択される治療用薬剤をそれぞれ含む約20〜約200個の複合体を含む、粒子。 - DSPE−PEG2000をさらに含む、請求項26に記載の粒子。
- 前記DSPE−PEG対前記複合体の比率が、重量で約1:1である、請求項27に記載の粒子。
- 請求項20に記載の粒子を形成するための方法であって、前記方法が、複数の請求項1に記載の複合体を、前記複合体を請求項20に記載の粒子に自己集合させるのに十分な条件下で、維持することを含む、前記方法。
- 前記複合体が、約1nM〜約1Mの濃度である、請求項29に記載の方法。
- PEG化脂質を、前記複数の複合体に添加することをさらに含む、請求項29に記載の方法。
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