JP2016531840A - 抗癌化学療法剤用のケージ化された白金ナノクラスタ - Google Patents
抗癌化学療法剤用のケージ化された白金ナノクラスタ Download PDFInfo
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- JP2016531840A JP2016531840A JP2016510669A JP2016510669A JP2016531840A JP 2016531840 A JP2016531840 A JP 2016531840A JP 2016510669 A JP2016510669 A JP 2016510669A JP 2016510669 A JP2016510669 A JP 2016510669A JP 2016531840 A JP2016531840 A JP 2016531840A
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Classifications
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Abstract
Description
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成する工程と、
(b)PtCl6 2−アニオン/デンドリマー複合体を含む混合物を所定時間インキュベートする工程と、
(c)PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成する工程と、
(d)デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物をフィルタに通過させて、デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得する工程と、
(e)濾液を凍結乾燥して、デンドリマーでケージ化された白金ナノクラスタ複合体を取得する工程とを含むケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(i)溶媒に、
(a)アミン終端デンドリマー又はヒドロキシル終端デンドリマーと、
(b)酸化白金を含み、アミン終端デンドリマー又はヒドロキシル終端デンドリマーの内部に閉じ込められる白金ナノクラスタと、
を含む上述のデンドリマーでケージ化された白金ナノクラスタ複合体を溶解させて溶液を形成し、
(ii)デンドリマーがアミンで終端された条件でPEGアルデヒドを溶液中に添加、又は、デンドリマーがヒドロキシル終端された条件でPEG−NH2を溶液中に添加し、
(iii)PEGアルデヒドをアミン終端デンドリマーの第一級アミンと反応させる、又は、PEG−NH2をヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する、二重ケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(a)治療に有効な量の上述の複合体と、
(b)医薬上許容される担体と、
を含む、医薬組成物に関する。
本明細書中に使用される用語は概して、本発明の文脈において、また各々の用語が使用される特定の文脈において、当該技術分野におけるそれらの通常の意味を有するものである。本発明を記載するために使用される特定の用語は、以下、又は本明細書中の他の部分で論じられ、本発明の記載に関わる実務者に付加的な手引きを提供するものである。便宜上、幾つかの用語を強調することもあり、例えば、イタリック及び/又は引用符を使用することもある。強調を使用しても用語の範囲及び意味に影響を与えることはなく、それが強調されるにせよされないにせよ、同様の文脈において用語の範囲及び意味は同じである。同じ事項を、2つ以上の方法で述べることがあることを理解されたい。したがって、ここで論じられる用語のいずれか1つ又は複数に、代替的な用語及び同義語を使用してもよく、また、用語がここで補足説明されるか又は述べられるかにせよされないにせよ、それに特殊な意義が課されることもない。幾つかの用語に対して同義語を提示している。1つ又は複数の同義語の詳説は、他の同義語の使用を排除するものではない。ここに述べられるあらゆる用語の用例を含む本明細書全体での用例の使用は、例示を目的とするにすぎず、本発明又は例を挙げた全ての用語の範囲及び意味を限定するものではない。同様に、本発明は本明細書中に与えられる様々な実施形態に限定されるものでもない。
HED=動物の投与量(mg/kg)×(動物の体重(kg)/ヒトの体重(kg))0.33
による計算によって得ることができることを開示している。HEDは、投与の経路等の他の因子に応じて様々な値をとることができる。例えばDCPNのi.v.投与では、マウス(20グラムBW)の投与量が16.6μmol/kgであれば、その際、HEDは16.6μmol/kg×(0.02/患者の体重)0.33と算出することができる。CPNのIT注射では、マウスの投与量が7.5mg/kgであれば、その際、HEDは7.5mg/kg×(0.02/患者の体重)0.33となる。
(a)アミン終端デンドリマーと、
(b)酸化白金を含み、アミン終端デンドリマーの内部(内側)に閉じ込められる白金ナノクラスタと、
から本質的になるか又はそれらからなる。
(a)治療に有効な量の上述の複合体と、
(b)医薬上許容される担体と、
を含む、医薬組成物に関する。
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成する工程と、
(b)PtCl6 2−アニオン/デンドリマー複合体を含む混合物を所定時間インキュベートする工程と、
(c)PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成する工程と、
(d)デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物をフィルタに通過させて、デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得する工程と、
(e)濾液を凍結乾燥して、デンドリマーでケージ化された白金ナノクラスタ複合体を取得する工程と、
を含む、上述のケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(i)溶媒に、
(a)アミン終端デンドリマー又はヒドロキシル終端デンドリマーと、
(b)アミン終端デンドリマー又はヒドロキシル終端デンドリマーの内部に閉じ込められた酸化白金を含む白金ナノクラスタと、
を含む上述のデンドリマーでケージ化された白金ナノクラスタ複合体を溶解して溶液を形成する工程と、
(ii)複合体がアミン終端デンドリマーを含む条件でPEGアルデヒドを溶液中に添加する、又は、複合体がヒドロキシル終端デンドリマーを含む条件でPEG−NH2を溶液中に添加する工程と、
(iii)PEGアルデヒドを、アミン終端デンドリマーの第一級アミンと反応させる、又は、PEG−NH2をヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する工程と、
を含む、二重ケージ化された白金ナノクラスタ複合体を合成する方法に関する。
CPNの合成及び特性解析。H2PtCl6(Acros、200μL、30μmol、150mM)及びK2PtCl4(UniRegion Bio-Tech、200μL、30μmol、150mM)をそれぞれ、G2NH2又はG2OH又はG2COOH(Aldrich、94.7μL、5μmol、20wt%メタノール溶液)を含有する20mLの脱イオン水に添加した。マイクロ波によって照射(CEM、Discover LabMate System、300W/120℃及び30分間)する前に、G2NH2又はG2OH又はG2COOHと、H2PtCl6又はK2PtCl4との混合物を室温で一晩インキュベートした。還元後、0.22μmメンブレンフィルタ(Millipore、PES膜、白金ナノクラスタ用)に通して沈殿した大きい白金ナノ粒子を濾過した。溶液を凍結乾燥させた後、約1mLの水に溶解させて、更に精製する必要がある。過剰なアニオン(PtCl6 2−及びPtCl4 2−)を更に除去するために、アニオン交換クロマトグラフィ(Merck、Fractogel EMD TMAE Hicap)を使用し、精製されたCPNとPNの凝集物(aggregations)が得られた。高分解能透過型電子顕微鏡(HRTEM、JEOL−2010)を用いて、CPNとPNの集合体のサイズを特定した。
本発明者らは、低世代のアミン終端デンドリマー(G2NH2)をケージとして使用し、特異的な幾何学的形状を有するアニオンを捕捉することにより、ケージ化されたPN(CPN、図1A、経路ii)を形成した。CPNは、追加される開裂性のPEGコロナ及びiRGD(CRGDKGPDC;配列番号1)等の標的可能な分子で更に改変されることで、腫瘍を標的化するとともに、外側のPEGコロナを取って抗癌化学療法剤にかかる腫瘍内活性化を作用させて悪性細胞に対して毒素を放出することができた(図1B)。
Claims (20)
- (a)デンドリマーと、
(b)酸化白金を含み、前記デンドリマーの内部に閉じ込められる白金ナノクラスタと、
(c)前記デンドリマーの表面を被覆するポリエチレングリコール(PEG)と、
を含む二重ケージ化された白金ナノクラスタ複合体。 - 前記酸化白金が、PtO、PtOH、PtO2、PtxOy、及びそれらの任意の組合せ(式中、x、yはそれぞれ0より大きい整数である)からなる群から選択される請求項1に記載の複合体。
- 前記デンドリマーがアミン終端デンドリマーである請求項1に記載の複合体。
- 前記PEGがシッフ塩基を通じて前記アミン終端デンドリマーの第一級アミンと結合する、請求項3に記載の複合体。
- 表面にpH応答性結合を含む請求項1に記載の複合体。
- 前記デンドリマーの表面上に吸収される腫瘍浸透ペプチドを更に含む請求項1に記載の複合体。
- pH5.0未満の条件下で、Pt2+イオン、PtCl4 2−イオン及び/又はPtCl6 2−イオンを放出する請求項1に記載の複合体。
- 前記白金ナノクラスタが、pH5.0未満の条件下で溶解性を示す請求項3に記載の複合体。
- 前記ナノクラスタが1.3nm未満の平均サイズを有する請求項1に記載の複合体。
- 前記デンドリマーが、世代−0(G−0)、世代−1(G−1)、世代−2(G−2)及び世代−3(G−3)デンドリマーからなる群から選択される請求項1に記載の複合体。
- 腫瘍細胞の成長を抑制する医薬品の製造における、請求項1〜10のいずれか一項に記載の二重ケージ化された白金ナノクラスタ複合体の使用。
- 請求項1〜10のいずれか一項に記載の二重ケージ化された白金ナノクラスタ複合体を合成する方法であって、
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成し、
(b)前記PtCl6 2−アニオン/デンドリマー複合体を含む前記混合物を所定時間インキュベートし、
(c)前記PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成し、
(d)前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む前記混合物をフィルタに通過させて、前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得し、
(e)前記濾液を凍結乾燥して前記デンドリマーでケージ化された白金ナノクラスタ複合体を取得し、
(f)前記デンドリマーでケージ化された白金ナノクラスタ複合体を溶媒に溶解して溶液を形成し、
(g)前記デンドリマーがアミン終端された条件でPEGアルデヒドを前記溶液中に添加、又は、前記デンドリマーがヒドロキシル終端された条件でPEG−NH2を前記溶液中に添加し、
(h)前記PEGアルデヒドを前記アミン終端デンドリマーの第一級アミンと反応させる、又は、前記PEG−NH2を前記ヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する、二重ケージ化された白金ナノクラスタ複合体を合成する方法。 - (a)アミン終端デンドリマーと、
(b)酸化白金を含むと共に0.22nmの標準偏差を伴う0.93nmの平均直径を有し、前記アミン終端デンドリマーの内部に閉じ込められる白金ナノクラスタと、
を含むケージ化された白金ナノクラスタ複合体。 - 請求項13に記載の複合体を合成する方法であって、
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成し、
(b)前記PtCl6 2−アニオン/デンドリマー複合体を含む前記混合物を所定時間インキュベートし、
(c)前記PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成し、
(d)前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む前記混合物をフィルタに通過させて、前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得し、
(e)前記濾液を凍結乾燥して、前記デンドリマーでケージ化された白金ナノクラスタ複合体を取得する、複合体を合成する方法。 - 前記還元する工程は、マイクロ波を照射して行う請求項12又は14に記載の方法。
- 前記インキュベートする工程は、室温で一晩行う請求項12又は14に記載の方法。
- 工程(e)は、余分なPtCl6 2−を除去することによって、前記デンドリマーでケージ化された白金ナノクラスタ複合体を精製することを更に含む請求項12又は14に記載の方法。
- 前記デンドリマーは、ポリアミドアミン(PAMAM)デンドリマーである請求項1〜10及び13のいずれか一項に記載の複合体。
- ヘキサクロロ白金酸アニオン及び/又はテトラクロロ白金酸アニオンを含まない請求項1〜10及び13のいずれか一項に記載の複合体。
- 癌細胞に対する細胞毒性を示す請求項1〜10及び13のいずれか一項に記載の複合体。
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