JP7372672B2 - 活性医薬成分の複合体 - Google Patents
活性医薬成分の複合体 Download PDFInfo
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- JP7372672B2 JP7372672B2 JP2019569803A JP2019569803A JP7372672B2 JP 7372672 B2 JP7372672 B2 JP 7372672B2 JP 2019569803 A JP2019569803 A JP 2019569803A JP 2019569803 A JP2019569803 A JP 2019569803A JP 7372672 B2 JP7372672 B2 JP 7372672B2
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Description
本出願は、2017年6月16日出願の米国仮出願第62/521,181号の優先権を主張し、該出願はあらゆる目的でその全内容が本明細書に組み込まれる。
本発明は、NIH(国立衛生研究所)により授与された認可番号CA199668号およびHD086195号のもと政府支援を受けて行われた。政府は本発明に対して一定の権利を有する。
ナノスケールでの薬剤送達システム(NDDS)は、活性医薬成分(API)を特定の病変へと標的指向的に送達し且つ制御放出(コントロールドリリース)するためにナノテクノロジーによって考案された。NDDSは、APIの溶解性を改善し、APIを分解から保護し、血液循環時間を延長し、健全な臓器に沿って副作用を誘発することなくそれらを腫瘍組織に特異的に運ぶことを可能にするため、NDDSの利用は、癌療法のための新規治療薬を創出する新たな希望を生み出すものと大いに期待されている。無機NDDSの臨床応用は、潜在的に累積する長期毒性のために抑えられていた。従って、科学者らは、主にリポソーム、ミセル、高分子ナノ粒子、タンパク質ベースのナノ粒子等をはじめとする有機NDDSの開発に多大な努力を払った。有機材料の優れた生体適合性と生分解性のおかげで、幾つかのナノ医薬、例えばパクリタキセル内封アルブミン製剤(アブラキサン)、リポソーム被覆ドキソルビシン(ドキシル)およびパクリタキセル内封高分子ミセル(ゲネキソール-PM)等が既に市販されている。それにもかかわらず、それらの有機NDDSはまだ低い封入能力(%DL、〔封入された薬剤/ナノ粒子重量〕×100として定義される)という欠点を有している。今までのところ、大部分の有機NDDSは20重量%以下の%DLを有すると報告されており、これは多量の非医薬成分が少量のAPIを送達させるために使用されることを意味し、このステップは巨大な資源を消費する。大部分のキャリアは非毒性であると主張されているが、この主張は安全閾値(基準値)の範囲内に限定される。より高い効能を達成するためにAPI量を増加させる必要がある時、非医薬成分の量がそれに従って増加され、安全閾値を超えることがあり、そのため毒性を示す可能性がある。例えば、最も認容されているポリマーのポリエチレングリコール(PEG)は、高濃度で投与すると或る程度の毒性を示す。
一実施形態では、本発明は式Iの化合物を提供する:
X-(L)-Y
上式中、Xは親水性治療薬であり、Lは存在しないかまたはリンカーであり、そしてYはポルフィリンもしくはその類似体を含む光活性化合物、または疎水性治療薬であり、ここで前記化合物はドキソルビシン-10-ヒドロキシカンプトテシンおよびイリノテカン-クロラムブシルを除く。
I.総論
本発明は、第一の活性医薬成分と、第二の活性医薬成分または光活性化合物(例えばポルフィリンまたはその誘導体)との一連の両親媒性複合体を提供する。両親媒性複合体は自己集合してナノ粒子を形成し、ナノ粒子は凝集してナノキャリアを形成する。ナノ粒子とナノキャリアは癌細胞によりまたは処置すべき他の細胞により吸収され、2つの活性抗癌剤を癌細胞に同時に送達する。対象の疾患または状態を治療するために複合体を投与することは、いずれか一方の治療薬を単独で投与する場合のFDAに認可された投与量よりも低い投与量での投与を可能にする。
「分配係数」または「logP」は、2つの不混和性液体、例えば水性溶媒(水)と非極性溶媒(しばしばオクタノール)中での化合物または物質の濃度の相対比を指す。不混和性液体が水とオクタノールである時、logP値が大きくなるほどより疎水性の化合物であることを示す。logPは次の式に従って算出される:
III.複合体(コンジュゲート)
X-(L)-Y
上式中、Xは親水性治療薬であり、Lは存在しないかまたはリンカーであり、そしてYはポルフィリンまたはその類似体を含む光活性化合物、または疎水性治療薬であり、ここで前記化合物はドキソルビシン-10-ヒドロキシカンプトテシンおよびイリノテカン-クロラムブシル以外のものである。
A.薬物-薬物複合体
幾つかの実施形態では、基Yは光活性化合物である。本発明において有用な光活性化合物には、限定されないが、ポルフィリン、ベンゾポルフィリン、コリン、クロリン、バクテリオクロロフィル、コルフィン、またはその誘導体が含まれる。
本発明の両親媒性化合物は自己集合して内部と外部を有するナノ粒子を形成し、ここで本発明の複合体の疎水性部分が内部にあり、そして該複合体の親水性部分がナノ粒子の外部上にある。幾つかの実施形態では、本発明は、本発明の複数の複合体を有するナノ粒子であって、内部と外部を含むナノ粒子を提供する。
本発明はまた、式Iの化合物並びに本発明のナノ粒子およびナノキャリアを使って疾病または状態を治療する方法も提供する。幾つかの実施形態では、本発明は疾病または状態を治療する方法であって、それを必要とする対象に、治療有効量の式Iの複合体または本発明のナノ粒子を投与し、それによって該疾病または状態を治療することを含む方法を提供する。
VI.イメージング方法と検出方法
本発明は、本発明の複合体、ナノ粒子またはナノキャリアとレーザーとのシステムも提供する。幾つかの実施形態では、本発明は、本発明の式Iの化合物またはナノ粒子とレーザーとのシステムを提供する。幾つかの実施形態では、該システムは式Iの化合物とレーザーとを含む。
材料と特徴付け
イリノテカンはBIOTANG Inc.(米国マサチューセッツ州)から購入した。フェオホルビドAはSanta Cruz Biotechnology社から購入した。N,N′-ジシクロヘキシルカルボジイミド(DCC)、4-(ジメチルアミノ)ピリジン(DMAP)、DCF-DA、MnCl2および全ての溶媒は、Sigma-Aldrich社(米国ミズーリ州)から購入した。一重項酸素検知試薬(緑)であるLyso-Tracker Greenと、一重項酸素検知試薬(緑)であるCellROXは、Thermo Fisher Scientific Inc.より購入した。細胞培養培地、ウシ胎仔血清、細胞培養皿およびプレートは、米国Corning Inc.から購入した。PDXグリオーマ腫瘍組織は、米国カリフォルニア州サンフランシスコのカリフォルニア大学の神経外科のDavid James博士研究室からの厚意によるものであった。合成化合物は、Bruker UltraFlextreme MALDI-TOF-MSおよび600 MHzのAvance III NMR分光計(Bruker社製、ドイツ)により分析した。透過型電子顕微鏡法(TEM)は、80 kV加速電圧を用いPhilips CM-120 TEM上で実施した。細胞レベルのレーザー処置は、広域カバーエリアを有するレーザー光源(Omnilux new-U)下で行った。生体外(in vitro)蛍光写真は、共焦点レーザー走査型顕微鏡法(CLSM、LSM810、Carl Zeiss製)によりキャプチャーした。in vitro磁気共鳴画像診断(MRI)は、Biospec 7T MRI装置(Bruler社製、ドイツ)上で実施した。
結果
ポルフィリン誘導体は、金属イオンをキレート化してマルチモーダル生体内イメージングを達成できるようにし、例えばMn2+キレート化PaはT1-MRIイメージングを実現化し、そして銅(64)はPaをPETで視覚化できるようにする。よって、マルチモーダルイメージング能力を拡張するために、Mn2+をPINにキレート化し、生体外でMRIイメージング機能を評価した。図5aと図5bに示されるように、Pa(PI分子中)の蛍光は、非キレート化相当物に比較すると、金属イオンのキレート化のために完全に消光された。図5cは、PINの濃度依存性MRIシグナル増強を示し、これはPINがMRIイメージング能力があることを示した。更にPINをU87-MG細胞と共にインキュベートし、その細胞をMRIイメージング用にアガロースゲル中に固定した。図5dに示されるように、Mn2+キレート化を有するPINは、明白にU87-MG細胞を可視化し、そして優れた弛緩率を達成した。これに基づき、本発明のポルフィリンベースのF/HAPINは、同様にマルチモーダルイメージング能力を実現化することができる。
薬物-薬物両親媒性複合体ベースのF/HAPIN。純粋な化学療法薬-薬物両親媒性複合体も、本発明にかかる自己集合機序に従う。本発明者らは、特定の刺激応答性リンカーも組み込まれている様々な種類の薬物-薬物両親媒性複合体を仮説的に設計した。この薬物-薬物両親媒性複合体は、ナノ粒子のような小型ミセルを形成することができ、更に大きなナノ粒子へと集成することができる。薬物-薬物ベースのF/HAPINは、異なる種類の純薬物から創製され、よって相乗的な治療効果を示す。下記はドキソルビシンベースの薬物-薬物両親媒性複合体であり、ここでドキソルビシンは両親媒性複合体の親水性部として働く。本発明にかかる自己集合メカニズムによれば、ドキソルビシンをイリノテカン、ダウノルビシン、イダルビシン、トポテカン等のような別の親水性薬物と置換することも可能である。疎水性部には、パクリタキセル、カバジタキセル、ドセタキセル、ビンブラスチンのような疎水性化学療法薬が選択された。薬物の親水性-疎水性は、それらのLogP値に基づいて決定され、一般に、LogP値が大きいほど親水性が大きいことを意味する。2つの薬物間のリンカーを別の刺激応答性化学結合、例えばpH応答性(ヒドラゾン、エステル結合、オルトエステル、イミン、シス-アコニチル、アセタール/ケタール)、酵素開裂性ペプチド(MMP-2/9、カスパーゼ-3/9、カテプシンB)、レドックス応答性(ジスルフィド結合)およびシス-ジオール/pH応答性(ボロン酸エステル)として設定することもできる。刺激応答性リンカーは特定の病巣において制御可能に放出させるために有益である。pH応答性リンカーの場合には、薬物-薬物集合ナノ粒子がEPR効果によって腫瘍組織中のリソソームに入ると、それらのリンカーは酸性条件下で破壊され、次いで2つの薬物を同時に放出するだろう。酵素開裂性ペプチドの場合、薬物-薬物複合体は腫瘍組織の近傍に来ると、それらが腫瘍組織中に過剰発現された対応する酵素の基質であるために、リンカーが切断され、次いで同様に薬剤が放出されるだろう。ジスルフィド結合のような別のリンカーの場合、それらは腫瘍中の過剰なGSHにより誘導されるレドックス条件に基づいて切断され得る。
50 mgのボルテゾミブ(BTZ)を10 mLのMeOH中に溶かし、次いで59.7 mgのクルクミン(CCM)を加えた。混合物を遮光下で4時間攪拌した。生成物をシリカゲルクロマトグラフィーにより精製した。質量分析により決定したBTZ-CCMの分子量は717.4であり、これは計算結果と同じであった。
実施例4からの複合体(1.18 mg)を1 mLのエタノールに溶かし、次いでその溶液を攪拌しながら2 mLの水に滴下添加した。その溶液を24時間連続して攪拌し、メタノールを蒸発させた後、サンプルをTEMとDLSにより測定した(図6)。BTZ-CCMナノ粒子は優良な球形を有し、水への分散性も良好であった。加えて、平均粒径は約108 nmであった(図6b)。
薬物放出
BTZ-CCMナノ粒子の薬物放出試験を透析法を用いて実施した。ナノ粒子溶液を透析カートリッジに注入し、室温で異なる(pHの)PBSに対して透析した。BTZ-CCMナノ粒子はpH感受性放出挙動を示し(図7)、pH値が7.4である時にはわずか15.3%のBTZが48時間でBTZ-CCMナノ粒子から放出された。その一方、pH値が5.0である時には88.6%までのBTZが48時間で放出された。既知の通り、ボロン酸エステルは、ボロン酸とジオールを生成することにより外部酸性環境に反応性である。ここでボロン酸エステル結合を含むBTZ-CCMナノ粒子はpH感受性を示し、それはナノ粒子が生理学的中性条件では非常に安定であり、酸性環境のもとでは迅速に2つの親薬物を放出できることを意味する。
BTZ-CCMナノ粒子が効率的に癌細胞内に入ることができるかどうかを確かめるため、蛍光イメージング法を使ってRPMI 8226細胞系において細胞取込み研究を行った。BTZ-CCMナノ粒子中に内包されたトレーサーDID色素(赤)を用いて、BTZ-CCMナノ粒子の位置を明らかにした。図8に示す通り、ブランク群と比較して、BTZ-CCMと共に4時間インキュベートした細胞は強い赤色蛍光を示した。これは、それらのナノ粒子がRPMI 8226細胞に容易に取り込まれ得ることを意味する。
プロドラッグナノ粒子であるBTZ-CCMは、親薬物と同等のまたは類似した抗腫瘍活性を維持する必要があるため、本発明者らは、48時間処置後のRPMI 8226とSKOV-3細胞の細胞生存率をMTSアッセイを使って調べた。図9に示されるように、BTZ-CCMナノ粒子は、RPMI 8226細胞とSKOV-3細胞についてそれぞれ0.3 ng/mLと20 ng/mLのIC50値を示す、用量依存性パターンにより両細胞の増殖を阻害することができた。RPMI 8226細胞に対するBTZ-CCMの曲線は、SKOV3細胞に対してはその効能がわずかに減少するけれども、BTZ単独でのものとほとんど重複している。従って、最終的なBTZ-CCMナノ粒子は遊離型BTZと対比して同様な抗癌作用を示す。
材料と装置。フェオホルビドaは、Santa Cruz Biotechnology社(米国テキサス州)から購入した。ドキソルビシンはLC Laboratories(米国マサチューセッツ州)から購入した。ヒドラジン、(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩)(EDC)、N-ヒドロキシスクシンイミド(NHS)、N,N′-ジシクロヘキシルカルボジイミド(DCC)、4-ジメチルアミノピリジン(DMAP)、2′,7′-ジクロロフルオレセインジアセタート(DCF-DA)、MnCl2、および全ての溶媒は、Sigma-Aldrich社(米国ミズーリ州)から購入した。一重項酸素センサーグリーン(SOSG)、Lyso-Tracker Deep RedおよびCellROXはThermo Fisher Scientific Inc.より購入した。合成化合物はBruker UltraFlextremeマトリックス支援レーザー脱着/イオン化時間飛行型質量分析法(MALDI-TOF-MS)、Thermo Electron LTQ-Orbitrap XL Hybrid電子噴射イオン化質量分析法(ESI-MS)および600 MHz Avance III核磁気共鳴(NMR)分光計(Bruker、ドイツ)により分析した。透過型電子顕微鏡法(TEM)は80 kVの加速電圧を用いるTalos L120C TEM(FEI)上で実施した。インビトロレーザー処置は、幅広いカバー領域を有する光源(Omnilux new-U)のもとで施行した。細胞蛍光画像は、共焦点レーザー走査型顕微鏡(CLSM、LSM810、Carl Zeiss社製)を用いてキャプチャした。磁気共鳴イメージング(MRI)はBiospec 7T MRIスキャナー(Bruker、ドイツ)上で実施した。アポトーシスと細胞ROS産生は、BD Fortessa 20カラーフローサイトメトリーにより評価した。ヒドロキシル化ポリエチレングリコール2000(PEG2000)はLaysan Bio Inc (米国アラバマ州)から購入した。
二重アルデヒド末端化PEGの合成と特徴付け。570 mgの4-ホルミル安息香酸(Formylbenonic acid)(5ミリモル)と206 mgのDCC(7ミリモル)を無水DCM中に溶かし、多数の白色沈澱が観察されるまで混合物を0℃で30分間攪拌した。次に、10 mLの無水DCM中の1000 mgのヒドロキシル化PEG2000(0.5ミリモル)と73 mgのDMAP(0.6ミリモル)を加えた。生じた混合物を周囲温度で24時間攪拌した。二元アルデヒド末端PEGを冷エーテルを用いた沈澱により精製し、透析チューブ(MWCOは1,000 Daである)を用いて更に透析した。次いでその溶液を凍結乾燥した。
Mn2+キレート化pPhD NPの調製。Mn2+キレート化は発表された方法に従って実施した。簡単に言えば、24.3 mgのPhy(40μモル)と25.2 mgのMnCl2(200μモル)、200μLのピリジンを含む2 mLのメタノールに溶かし、そして反応液を2時間還流させた。Mn2+キレート化Phyを抽出(水に対するDCM)により5回精製した。キレート化しなかったMn2+はMilli Q水中に溶かし、除去した。Mn2+キレート化Phyは有機層(DCM)にとどまり、それをロータリーエバポレーターにより乾燥した。次いで、マンガンイオンがキレート化したPhyを用いてPhDモノマーを合成し、上述した手順を用いてpPhD NPを作製した。
方法
材料の光学測定。UV-可視分光計(UV-1800、島津製)を用いてUV-可視スペクトルを採集した。全ての材料と化合物について、200 nm~800 nmの範囲のもとに吸光度を採集した。蛍光スペクトルは、蛍光分光計(RF-6000、島津製)により取得した。Phyには、412 nmの励起波長を使用し、そしてDOXには、励起波長を488 nmに設定した。PhDモノマーまたはナノ製剤の蛍光特性を調べるために、両方の励起波長を使用した。
腫瘍体積=長さ×(幅/2)2
結果
材料。フェオホルビドA(Pa)はSanta Cruz Biotechnology社から購入した。イリノテカン(Ir)はBIOTANG Inc.(米国マサチューセッツ州)から購入した。DCF-DAと全ての溶媒はSigma-Aldrich社(米国ミズーリ州)から購入した。
方法
照射による生体外(in vitro)ROS産生および熱発生の評価。様々な濃度のRBC-PIまたはPI NPSsを96ウェルプレート中に入れ、0.8 w/cm2の680 nmレーザー(中国、上海)で3分間露光した。熱発生は、NIR温度カメラ(FLIR、米国カリフォルニア州サンタバーバラ)により測定した。ROS産生は、指示薬としてDCF-DAを使って測定した。簡単に言えば、種々の濃度のRBC-RIまたはPI NPSsを50μM DCFH-DA(発光溶液)と共にインキュベートし、続いて光線処置した(680 nm、0.8 W/cm2で3分間)。蛍光をSpectraMax M3マイクロプレートリーダー(Molecular Devices、LLC、CA)により定量した。
長さ×幅2/2(mm3)。
生物模倣性(バイオミミクリー)RBC-PI複合体の調製と特徴付け。本発明者らは以前に、疎水性光増感剤のフェオホルヒドA(Pa)と比較的親水性の抗腫瘍薬であるイリノテカン(Ir)との複合体から自己集合した新規な完全APIナノ粒子(PI)を開発した。その両親媒性に基づくと、PIは賦形剤が無くてもナノ粒子に自己集合することができ、光線力学療法、光熱療法および化学療法を含む3併用療法に利用することができた。しかしながら、PI NPSsはあまり安定でなく、それらの強い正電荷(+42 mV)が理想より低い(less-ideal)血液循環時間(9.1±2.7時間)を引き起こし、よって癌療法に十分な可能性を与えた。ナノ粒子の循環時間を大幅に延長するためにRBC細胞膜生物模倣性表面修飾を使うという興味深い方策によりアイデアを得て、本発明者らは最初に細胞膜に導入してPI NPSベースの薬物自己送達システムを修飾し、それらの安定性、PKプロファイルおよび抗治療指数を改善することとした。
Claims (20)
- 式I:
X-(L)-Y
[式中、
Yはフェオホルビド-aであり、
(a)Xはイリノテカンであり、Lは存在しない;または
(b)Xはドキソルビシンであり、Lはヒドラゾンである。]
の複合体。 - 次の構造:
- 次の構造:
- ナノ粒子が内部と外部を含む、複数の、請求項1~3のいずれか一項に記載の複合体を含むナノ粒子。
- 前記ナノ粒子の外部が安定化ポリマー、細胞膜または標的指向性リガンドの少なくとも1つを含む、請求項4に記載のナノ粒子。
- 前記ナノ粒子の外部がポリエチレングリコール、ヒアルロン酸、細胞膜、RGD、CRGDK、葉酸またはガラクトースの少なくとも1つを含む、請求項4または5に記載のナノ粒子。
- 前記外部がポリエチレングリコールを含む、請求項4~6のいずれか一項に記載のナノ粒子。
- 前記外部が赤血球小胞を含む、請求項4~6のいずれか一項に記載のナノ粒子。
- 複数のナノ粒子が自己集合してナノキャリアを形成する、請求項4~6のいずれか一項に記載のナノ粒子。
- 前記ナノキャリアのナノ粒子が架橋結合される、請求項4~9のいずれか一項に記載のナノ粒子。
- 請求項4~10のいずれか一項に記載のナノ粒子の調製方法であって、複数の、請求項1~3のいずれか一項に記載の複合体が自己集合しそしてナノ粒子を形成するのに適した条件下で、複数の前記複合体を含む反応混合物を形成させることを含む、方法。
- 治療有効量の請求項1~3のいずれか一項に記載の複合体または請求項4~10いずれか一項に記載のナノ粒子を含む、対象における疾病または状態を治療するための組成物。
- 前記疾病または状態が癌である、請求項12に記載の組成物。
- 前記疾病または状態が癌腫、グリオーマ、中皮腫、黒色腫、リンパ腫、白血病、腺癌、乳癌、卵巣癌、子宮頸癌、グリア芽腫、白血病、リンパ腫、前立腺癌、およびバーキットリンパ腫、頭頸部癌、結腸癌、結腸直腸癌、非小細胞肺癌、小細胞肺癌、食道癌、胃癌、膵臓癌、肝胆道癌、胆嚢癌、小腸癌、直腸癌、腎臓癌、膀胱癌、前立腺癌、陰茎癌、尿道癌、精巣癌、子宮頸癌、膣癌、子宮癌、卵巣癌、甲状腺癌、副甲状腺癌、腺癌、膵臓内分泌癌、カルチノイド腫瘍、骨肉腫、皮膚癌、網膜芽腫、多発性骨髄腫、ホジキンリンパ腫、または非ホジキンリンパ腫である、請求項12または13に記載の組成物。
- 前記治療有効量が、複合体化していない治療薬の治療有効量よりも低い用量である、請求項12~14のいずれか一項に記載の組成物。
- 前記対象が、前記複合体の光活性化合物を励起させるのに十分なエネルギーと波長の放射線に更に露光される、請求項12~15のいずれか一項に記載の組成物。
- レーザーにより電磁放射線が提供される、請求項16に記載の組成物。
- 有効量の請求項1~3のいずれか一項に記載の複合体または請求項4~10のいずれか一項に記載のナノ粒子を含む、対象における組織または臓器のイメージングのための薬剤であって、
該複合体またはナノ粒子は前記組織または臓器中で濃縮され、
前記組織または臓器は適当な装置を使ってイメージングされる、薬剤。 - 有効量の請求項1~3のいずれか一項に記載の複合体または請求項4~10のいずれか一項に記載のナノ粒子を含む、放射線が第一の波長で適用されている対象において腫瘍を検出するための医薬組成物であって、前記複合体またはナノ粒子から放射された任意の放射線が検出され、それにより腫瘍が検出される、医薬組成物。
- 請求項1~3のいずれか一項に記載の複合体とレーザーとを含むシステム。
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AU2018283383A1 (en) | 2020-02-06 |
AU2023203791A1 (en) | 2023-07-13 |
US20210138084A1 (en) | 2021-05-13 |
AU2018283383B2 (en) | 2023-03-16 |
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WO2018232334A1 (en) | 2018-12-20 |
JP2023156449A (ja) | 2023-10-24 |
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