JP2019527740A - リジン−尿素−グルタメートファーマコフォアを含む修飾デキストラン複合体 - Google Patents
リジン−尿素−グルタメートファーマコフォアを含む修飾デキストラン複合体 Download PDFInfo
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- JP2019527740A JP2019527740A JP2018566546A JP2018566546A JP2019527740A JP 2019527740 A JP2019527740 A JP 2019527740A JP 2018566546 A JP2018566546 A JP 2018566546A JP 2018566546 A JP2018566546 A JP 2018566546A JP 2019527740 A JP2019527740 A JP 2019527740A
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Abstract
Description
本発明は、グルタメート−尿素−リジンファーマコフォアを含むグアニジン−デキストラン複合体などの修飾デキストラン複合体、および当該複合体の調製方法に関する。本発明の複合体は、前立腺特異的膜抗原(PSMA)の発現に関連する疾患または状態の治療または診断に使用され得る。
ヒドロキシポリマーは、糖ポリマーの一群であり、複数の水酸基を構成し、活性化され続いて効果的な化合物の異なる部分で都合よく置換され得る。デキストランは、製薬工業において最も頻繁に使用されるヒドロキシポリマーの1つであり、例えば血液量減少性ショック(chock)の予防、塞栓症の予防および微小循環の改善のための薬学的使用が確立されている。デキストランおよびその非毒性特性ならびに高い耐性は、非常によく報告されている(AS Segal, 1964 In: Modern medical monographs, ed. Wright, IS, Green & Stratton, NY, London, pp 5-17。従って、それは薬学的に適用可能なヒドロキシポリマーの例としてしばしは使用される。
本発明は、リジン−尿素−グルタメートファーマコフォアを含む修飾デキストラン複合体に関する。
放射性核種-リガンド複合体に結合したグルタメート-尿素-グルタメート(GUG)またはグルタメート-尿素-リジン(GUL)認識要素を含むいくつかの化合物がPSMAに対して高い親和性を示すことが以前に示されている。本発明者らは、PSMAタンパク結合グルタメート-尿素-リジントリペプチドが、遊離アミノ基を有する化合物とさらに結合され得る修飾デキストランと結合された複合体を発明した。これらの化合物は、細胞増殖抑制剤または診断/治療放射性核種などの種々のリガンドを含む。本発明の修飾デキストラン複合体は、PSMAを発現する癌の非侵襲性画像化、選択的標的化および治療のための魅力的な経路を提供する。
複合体合成
物質
デキストラン40(PhEUR; 10kD-500kD、好ましい40kDまたは70kD)(Pharmacosmos AS、デンマーク)を複合体骨格として用いた。メタ過ヨウ素酸ナトリウム(Merck AG、ダルムシュタット、ドイツ)を酸化/活性化のために用いた)。アミノグアニジン、L-リジン(Sigma-Aldrich、スウェーデン)およびPSMAリガンドグルタメート-尿素-リジン(Peptides & Elephants、受託合成)を結合のために用いた。シアノ水素化ホウ素ナトリウム(Sigma Aldrich、ストックホルム、スウェーデン)を還元的アミノ化のために用いた。PD-10使い捨てSephadex G-25カラムを分離および精製のために用いた(G&E Biotech AB、スウェーデン)。FITCはSigma Aldrichからのものであった。
30mgのデキストランを、1 mlの蒸留H2O中、18mgの過ヨウ素酸ナトリウムと混合し、そしてpHをH2SO4で1.6に調整した。混合物を、暗闇中、磁気攪拌機でRTで45分間インキュベートした。
30 mgの活性化デキストランを1 mlのpH 7.4の0.2 Mリン酸ナトリウム緩衝液中の20 mgのGlut-尿素-リジン + 5 mgのシアノ水素化ホウ素ナトリウムと混合し、次いで暗闇中、磁気攪拌機でRTで120分間インキュベートした。120分後、12 mgのアミノグアニジンおよび12 mgのリジンを加え、そしてインキュベーションをさらに60分間続けた。合計4 hのインキュベーション後、次いで溶液をpH 9.5の20 mMホウ酸緩衝液を溶出液として用いてPD-10カラムで精製した。
1mLのpH 9.5のホウ酸緩衝液中の15 mgの複合体を、50 μgのFITCと混合し、そして暗闇中、RTで18 hインキュベートした。インキュベーション後、複合体をPD10カラムで精製し、そしてpH 6の酢酸ナトリウム中に溶出した。
アメリカンタイプカルチャーコレクション(ATCC, USA)から得たヒト転移性前立腺癌細胞株22Rv1、DU145およびPC3を用いた。細胞株をRPMI 1640(Sigma)を含む5 mlディッシュ(Falcon)中で培養した。2 mMグルタミン(Sigma)、10 %ウシ胎仔血清(Life Technologist)および1 %ペニシリン/ストレプトマイシン(Gibco)を培地に加えた。細胞を加湿空気および5 % CO2を有する37℃インキュベーター中で保持した。培養培地を1週間に2回交換した。細胞をトリプシン(0.5g)-EDTA(0.2g)(Sigma, USA)処理によってディッシュから取り出した。
実施例は、本発明によるグアニジン-デキストラン-グルタメート-尿素-リジンPSMA結合複合体が腫瘍細胞において選択的に蓄積されることを実証するのに役立つ。図1aは、Lig_PSMA-DX_FITC複合体がPSMA陽性腫瘍細胞22Rv1に結合することができることを示し、一方図1bは、Lig_PSMA-DX-FITC複合体がPSMAを発現しないDU145細胞に結合しないことを実証する。図3は、Lig_PSMA-DX_FITC複合体のPSMA陽性腫瘍細胞22Rv1への結合が過剰量の遊離グルタミン−尿素−リジンによって阻害され得ることをさらに示す。
活性化および複合体化
30mgのデキストランを、1 mlの蒸留H2O中、18mgの過ヨウ素酸ナトリウムと混合し、そしてpHをH2SO4で1.6に調整した。混合物を、暗闇中、磁気攪拌機でRTで45分間インキュベートした。活性化後、混合物をPD10 sephadexカラムで精製し、そして精製および活性化したデキストランをpH 6,5の0.2M酢酸ナトリウム緩衝液中に溶出した。
30 mgの活性化デキストランを2 mlのpH 6.4の0.2 M酢酸ナトリウム緩衝液中の40 mgのGlut-尿素-リジン + 10 mgのシアノ水素化ホウ素ナトリウムと混合し、次いで暗闇中、磁気攪拌機でRTで180分間インキュベートした。180分後、40mgのDOTAを加え、そしてインキュベーションを一晩続けた。インキュベーション後、次いで溶液をpH 6の0.2M酢酸ナトリウム緩衝液を溶出液として用いて2つのPD-10カラムで精製した(各カラムで1mLの混合物を精製した)。精製した複合体からサンプルを取り、そして分光光度計でA280で測定した。吸光度を書き留め、そしてDOTA標準曲線と比較し、そして置換の程度を計算することができた。
Claims (17)
- リジン−尿素−グルタメートファーマコフォアを含むことを特徴とする修飾デキストラン複合体。
- デキストラン部分が少なくとも1つの遊離アミノ基を有する化合物で置換されていることを特徴とする請求項1に記載の修飾デキストラン複合体。
- デキストラン部分がグアニジン化合物で置換されていることを特徴とする請求項2に記載の修飾デキストラン複合体。
- デキストラン部分がガドリニウム標識化金属キレートで置換されていることを特徴とする請求項2に記載の修飾デキストラン複合体。
- デキストラン部分に他のリガンドでの置換をさらに含むことを特徴とする請求項1〜4のいずれかに記載の修飾デキストラン複合体。
- 他のリガンドが治療化合物、細胞増殖抑制薬およびガンマ、ベータまたはアルファ放射性核種をキレート化し得る放射性金属キレーターからなる群より選ばれることを特徴とする請求項5に記載の修飾デキストラン複合体。
- 放射性核種がガンマ放射(テクネチウム-99m)Tc(CO)3キレート錯体、ベータ放射(レニウム-186/188)Re(CO)3キレート錯体またはアルファ放射性核種キレート錯体であることを特徴とする請求項6に記載の修飾デキストラン複合体。
- 前立腺特異的膜抗原(PSMA)結合複合体であることを特徴とする請求項1〜7のいずれかに記載の修飾デキストラン複合体。
- 全身的、すなわち静脈内投与によって投与されることを特徴とする請求項1〜8のいずれかに記載の修飾デキストラン複合体。
- 腹腔への投与などにより局所的または部位局所的に、あるいは全身投与のために静脈内に投与されることを特徴とする請求項1〜8のいずれかに記載の修飾デキストラン複合体。
- 癌の治療、画像化または診断に使用するための請求項1〜10のいずれかに記載の修飾デキストラン複合体。
- 癌が、前立腺癌、腎臓癌、膵臓癌、乳癌、結腸癌、膀胱癌、精巣癌、黒色腫、グリア芽腫および軟部組織肉腫を含む悪性腫瘍を含むことを特徴とする請求項11に記載の修飾デキストラン複合体。
- 癌が前立腺癌であることを特徴とする請求項12に記載の修飾デキストラン複合体。
- 請求項1〜12のいずれかに記載の修飾デキストラン複合体および少なくとも1つの薬学的に受容可能なアジュバントを含むことを特徴とする殺腫瘍組成物。
- 請求項1〜13のいずれかに記載の修飾デキストラン複合体、その薬学的に受容可能な塩または溶媒和物および薬学的に受容可能な賦形剤を含む医薬製剤。
- 請求項14に記載の組成物または請求項5に記載の製剤の治療有効量をそのような治療を必要とする被検体に投与することを含む、被検体における癌の治療方法。
- 少なくとも1つの遊離アミノ基を有するグアニジン化合物が活性化デキストランおよびグルタミン−尿素−リジンと混合されることを特徴とする、請求項1〜3または5〜13のいずれかに記載の修飾デキストラン複合体の製造方法。
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