JP2017521371A - ナノ粒子薬物コンジュゲート - Google Patents
ナノ粒子薬物コンジュゲート Download PDFInfo
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Abstract
Description
本出願は、それぞれ2014年5月29日および2014年12月19日に出願された米国仮特許出願第62/004,738号および同第62/094,923号の優先権および利益を主張し、それらの全体を本明細書において参考として援用する。
本発明は、一般に、がんおよび他の疾患の検出、防止および治療のための治療剤の送達(例えば、標的薬物放出)用のナノ粒子コンジュゲートに関する。
定義
詳細な説明
試薬:
フラッシュクロマトグラフィー:
分析的HPLC:
分取HPLC:
核磁気共鳴(NMR);
トリプシンでの薬物放出アッセイ:
カテプシンBでの薬物放出アッセイ:
NDC安定性アッセイ:
H1650細胞でのホスホEGFRアッセイ:
O−des−モルホリノ−ゲフィチニブ、dMGの調製(図12(スキーム3)の8):
N−(tert−ブチルオキシカルボニル)−アミノプロピル−dMGの合成(図12(スキーム3)の9):
アミノプロピル−O−des−モルホリノ−ゲフィチニブ、APdMGの調製(図1Aおよび図12(スキーム3)の1):
9−フルオレニルメトキシカルボニル−N−アミド−dPEG2−アミノプロピル−dMG、Fmoc−dPEG2APdMGの調製(図13(スキーム4)の10):
アミノ−dPEG2−アミノプロピル−dMG、dPEG2APdMGの調製(図1Aおよび図13(スキーム4)の2):
Boc−N−アミノ−(dPEG2)3−Phe−Arg(Pbf)−OHの調製(図14(スキーム5)の11):
Boc−N−アミド−(dPEG2)3−Phe−Arg(Pbf)−APdMGの調製(図14(スキーム5)の12):
Boc−N−アミド−(dPEG2)3−Phe−Arg(Pbf)−dPEG2APdMGの調製(図14(スキーム5)の13):
H2N−(dPEG2)3−Phe−Arg−APdMGの調製(スキーム6の14):
H2N−(dPEG2)3−Phe−Arg−(dPEG2)−APdMGの調製(図14(スキーム5)の15):
S−アセチル−メルカプトアセトアミド−(dPEG2)3−Phe−Arg−APdMGの調製(図14(スキーム5)の16):
S−アセチル−メルカプトアセトアミド−(dPEG2)3−Phe−Arg−dPEG2APdMGの調製(図14(スキーム5)の17):
メルカプトアセトアミド−(dPEG2)3−Phe−Arg−APdMG、Phe−Arg−APdMGの調製(図1Bおよび図14(スキーム5)の3):
メルカプトアセトアミド−(dPEG2)3−Phe−Arg−dPEG2APdMG、Phe−Arg−dPEG2APdMGの調製(図1Cおよび図14(スキーム5)の4):
Fmoc−Lys(Mtt)−PABOHの調製(図15(スキーム6)の18):
Fmoc−Phe−Lys(Mtt)−PABOHの調製(図15(スキーム6)の19):
Fmoc−Phe−Lys(Mtt)−PABC−APdMGの調製(図15(スキーム6)の21):
Mmt−S−dPEG8−Phe−Lys(Mtt)−pABC−dMGの調製(図15(スキーム6)の22):
HS−dPEG8−Phe−Lys−PABC−アミノプロピル−dMGの調製(図15(スキーム6)の5):
C’ドット−(Cy5)−PEG−マレイミドの調製:
C’ドット−(Cy5)−PEG−Phe−Arg−dPEG2−Gly−D−Tyr−APdMGの調製:
C’ドット−(Cy5)−PEG−Phe−Lys−PABC−Gly−D−Tyr−APdMGの調製:
C’ドット−(Cy5)−PEG−Phe−Arg−dPEG2−Gly−D−Tyr−アミノプロピル−APdMGの放射性ヨウ素化物の調製:
例えば、本発明は以下の項目を提供する。
(項目1)
ナノ粒子(例えば、1nm〜25nmの範囲内の直径を有する);
リンカー部分;および
薬物部分(例えば、その任意の類似体を含むダサチニブまたはゲフィチニブ)
を含むナノ粒子薬物コンジュゲート(NDC)であって、
前記ナノ粒子が、有機ポリマー(例えば、前記有機ポリマーは、少なくとも1つのリンカー−薬物構築物に付着した少なくとも1つの二官能化マレイミドシリル−ポリエチレングリコール基を含む)でコーティングされており、
前記薬物部分およびリンカー部分が、前記ナノ粒子と共有結合的に連結する(例えば、前記リンカー部分によって)切断可能な(例えば、プロテアーゼによって)リンカー−薬物構築物を形成する(例えば、平均の薬物部分とナノ粒子との比は1〜20の範囲である)、ナノ粒子薬物コンジュゲート(NDC)。
(項目2)
前記リンカー部分が、1つまたは複数のアミノ酸(例えば、ペプチドまたはポリペプチド)(例えば、1〜10個のアミノ酸)を含む、項目1に記載のNDC。
(項目3)
前記リンカー部分が、
(アミノ−(スペーサー) x ) y −ペプチドまたは(スペーサー) z −ペプチド[例えば、ジペプチド(例えば、フェニルアラニン−アルギニン(Phe−Arg)またはフェニルアラニン−リシン(Phe−Lys))]を含み、
前記スペーサーが、2〜50個の原子を有しており(例えば、前記スペーサーはPEGである)、
xが1〜5の整数であり、
yが1〜5の整数であり、
zが5〜15の整数であり、
前記リンカー部分が、前記リンカー部分と前記薬物部分の間に分解可能な部分(例えば、アミド結合)を含む(例えば、プロテアーゼの存在下での前記薬物部分の切断を可能にする)、項目2に記載のNDC。
(項目4)
前記リンカー部分が、ペプチドと前記薬物部分の間にスペーサー(例えば、ポリエチレングリコール(PEG))、PEG 2 、パラ−アミノベンジルオキシカルバメート(PABC))を含む、項目1〜3のいずれか一項に記載のNDC。
(項目5)
蛍光化合物(例えば前記ナノ粒子のコア内部で、例えば前記ナノ粒子と会合している)をさらに含む、前記項目のいずれかに記載のNDC。
(項目6)
放射性標識をさらに含む、前記項目のいずれかに記載のNDC。
(項目7)
前記リンカー部分が、プロテアーゼ(例えば、セリンプロテアーゼ(例えば、トリプシン)、システインプロテアーゼ(例えば、カテプシンB))結合時にC末端での加水分解を受け、それによって前記ナノ粒子から前記薬物部分を放出させることができる、前記項目のいずれか一項に記載のNDC。
(項目8)
前記薬物部分が、受容体チロシンキナーゼ(RTK)阻害剤(例えば、前記薬物部分の活性結合部位の基本的な化学構造を乱すことなく、前記リンカー部分への付着をもたらすように修飾された、その任意の類似体(例えば、その任意の薬学的および/または治療的均等物)を含むダサチニブまたはゲフィチニブ)を含む、前記項目のいずれか一項に記載のNDC。
(項目9)
1〜20の標的化部分(例えば、環状アルギニルグリシルアスパラギン酸(cRGD))をさらに含み、前記標的化部分が腫瘍細胞上の受容体と結合する、前記項目のいずれか一項に記載のNDC。
(項目10)
セラノスティックである、項目8に記載のNDC。
(項目11)
蛍光化合物がCy5.5である、項目4に記載のNDC。
(項目12)
前記薬物部分が放射性標識に付着している、項目5に記載のNDC。
(項目13)
前記ナノ粒子が、シリカベースのコア、および前記コアの少なくとも一部を取り囲むシリカシェルをさらに含む、前記項目のいずれかに記載のNDC。
Claims (13)
- ナノ粒子(例えば、1nm〜25nmの範囲内の直径を有する);
リンカー部分;および
薬物部分(例えば、その任意の類似体を含むダサチニブまたはゲフィチニブ)
を含むナノ粒子薬物コンジュゲート(NDC)であって、
前記ナノ粒子が、有機ポリマー(例えば、前記有機ポリマーは、少なくとも1つのリンカー−薬物構築物に付着した少なくとも1つの二官能化マレイミドシリル−ポリエチレングリコール基を含む)でコーティングされており、
前記薬物部分およびリンカー部分が、前記ナノ粒子と共有結合的に連結する(例えば、前記リンカー部分によって)切断可能な(例えば、プロテアーゼによって)リンカー−薬物構築物を形成する(例えば、平均の薬物部分とナノ粒子との比は1〜20の範囲である)、ナノ粒子薬物コンジュゲート(NDC)。 - 前記リンカー部分が、1つまたは複数のアミノ酸(例えば、ペプチドまたはポリペプチド)(例えば、1〜10個のアミノ酸)を含む、請求項1に記載のNDC。
- 前記リンカー部分が、
(アミノ−(スペーサー)x)y−ペプチドまたは(スペーサー)z−ペプチド[例えば、ジペプチド(例えば、フェニルアラニン−アルギニン(Phe−Arg)またはフェニルアラニン−リシン(Phe−Lys))]を含み、
前記スペーサーが、2〜50個の原子を有しており(例えば、前記スペーサーはPEGである)、
xが1〜5の整数であり、
yが1〜5の整数であり、
zが5〜15の整数であり、
前記リンカー部分が、前記リンカー部分と前記薬物部分の間に分解可能な部分(例えば、アミド結合)を含む(例えば、プロテアーゼの存在下での前記薬物部分の切断を可能にする)、請求項2に記載のNDC。 - 前記リンカー部分が、ペプチドと前記薬物部分の間にスペーサー(例えば、ポリエチレングリコール(PEG))、PEG2、パラ−アミノベンジルオキシカルバメート(PABC))を含む、請求項1〜3のいずれか一項に記載のNDC。
- 蛍光化合物(例えば前記ナノ粒子のコア内部で、例えば前記ナノ粒子と会合している)をさらに含む、前記請求項のいずれかに記載のNDC。
- 放射性標識をさらに含む、前記請求項のいずれかに記載のNDC。
- 前記リンカー部分が、プロテアーゼ(例えば、セリンプロテアーゼ(例えば、トリプシン)、システインプロテアーゼ(例えば、カテプシンB))結合時にC末端での加水分解を受け、それによって前記ナノ粒子から前記薬物部分を放出させることができる、前記請求項のいずれか一項に記載のNDC。
- 前記薬物部分が、受容体チロシンキナーゼ(RTK)阻害剤(例えば、前記薬物部分の活性結合部位の基本的な化学構造を乱すことなく、前記リンカー部分への付着をもたらすように修飾された、その任意の類似体(例えば、その任意の薬学的および/または治療的均等物)を含むダサチニブまたはゲフィチニブ)を含む、前記請求項のいずれか一項に記載のNDC。
- 1〜20の標的化部分(例えば、環状アルギニルグリシルアスパラギン酸(cRGD))をさらに含み、前記標的化部分が腫瘍細胞上の受容体と結合する、前記請求項のいずれか一項に記載のNDC。
- セラノスティックである、請求項8に記載のNDC。
- 蛍光化合物がCy5.5である、請求項4に記載のNDC。
- 前記薬物部分が放射性標識に付着している、請求項5に記載のNDC。
- 前記ナノ粒子が、シリカベースのコア、および前記コアの少なくとも一部を取り囲むシリカシェルをさらに含む、前記請求項のいずれかに記載のNDC。
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