JP7467548B2 - Pegmema及び薬物担持ポリマーセグメントから構成される自己集合化ジブロックコポリマー - Google Patents
Pegmema及び薬物担持ポリマーセグメントから構成される自己集合化ジブロックコポリマー Download PDFInfo
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- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Description
・R1及びR2は、独立して、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・xは、1~100の自然数である
・yは、1~100の自然数である
・nは、1~50の自然数である
・Lは、切断可能なリンカーであるか、又はLは、ヌルであってもよい
・Dは、コンブレタスタチン、5-フルオロウラシル、ゲムシタビン、クロロキン、及びドキソルビシンを含む群から選択される治療薬である
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
・R1及びR2は、独立して、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・xは、1~100の自然数である
・yは、1~100の自然数である
・nは、1~50の自然数である
・Lは、切断可能なリンカーであるか、又はLは、ヌルであってもよい
・Dは、コンブレタスタチン、又は5-フルオロウラシル、又はゲムシタビン、又はクロロキン、又はドキソルビシンである治療薬である
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
・R1及びR2は、独立して、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・xは、1~100の自然数である
・yは、1~100の自然数である
・nは、1~50の自然数である
・Lは、切断可能なリンカーであるか、又はLは、ヌルであってもよい
・Dは、コンブレタスタチン、又は5-フルオロウラシル、又はゲムシタビン、又はクロロキン、又はドキソルビシンである治療薬である
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
式中、
・R1は、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・nは、1~50の自然数である
式IIaのポリマーを得、
式中、
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
・式中、R2は、H又はCH3から選択される
・Lは、切断可能なリンカーである、又はLは、ヌルであってもよい
・Dは、コンブレタスタチン、5-FU、ゲムシタビン、クロロキン、ドキソルビシンを含む群から選択され、式Iのポリマー-薬物コンジュゲートを得る治療薬である。
式中、
・R1は、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・nは、1~50の自然数である
式IIaのポリマーを得、
式中、
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
・式中、R2は、H又は-CH3から選択される
・Lは、切断可能なリンカーであるか、又はLは、ヌルであってもよい
式IIbに示されるようなコポリマーを得る
・式中、xは、1~100の自然数であり
・yは、1~100の自然数である
式中、
・R1は、H又は-CH3から選択される
・R3は、-H又は-CH3から選択される
・nは、1~50の自然数である
式IIaのポリマーを得、
式中、
・Aは、末端基であるか、又はAは、ヌルであってもよい
・Bは、末端基であるか、又はBは、ヌルであってもよい
・式中、R2は、H又は-CH3から選択される
・Lは、切断可能なリンカーである、又はLは、ヌルであってもよい
・Dは、コンブレタスタチン、5-FU、ゲムシタビン、クロロキン、ドキソルビシンを含む群から選択され、ブロックコポリマーを得る治療薬であり、次いで、(iii)形成されたブロックコポリマーを標的部分と反応させて、式Iに示されるポリマー-薬物コンジュゲートを得る。
式中;
-xは、1~100の自然数である、
-yは、1~100の自然数である、
-R1及びR2は、独立して、H又は-CH3から選択される、
-R3は、-H又は-CH3から選択される
-nは、1~50の自然数である、
-Lは、切断可能なリンカーである、又はLは、ヌルであってもよい
-Aは、末端基であるか、又はAは、ヌルであってもよい
-Bは、末端基であるか、又はBは、ヌルであってもよい。
以下の例は、式Iのポリマー-薬物コンジュゲート及びそれらのポリマー集合体の段階的調製を提供する。
コンブレタスタチン-A4(300mg、0.95mmol)、トリエチルアミン(TEA、191mg、1.89mmol)、塩化メタクリロイル(198mg、1.89mmol)をN2下で25mLの丸底フラスコ中で乾燥ジクロロメタン(DCM、10mL)に溶解した。反応液を室温で16時間撹拌した。粗生成物を飽和NaHCO3(20mL×2)及び蒸留水(20mL×2)で抽出した。有機層をNa2SO4で乾燥し、溶媒を蒸発させた。CombMAモノマーを、ヘキサンを用いたシリカカラムクロマトグラフィーを使用して精製した。
4-シアノペンタン酸ジチオペンタのアート(CPDB)は、CTAであり、このCTAを以下の手順に従って反応性官能基であるN-ヒドロキシスクシンイミド(NHS)で修飾した。
可逆的付加-開裂連鎖移動(RAFT)重合をPOEGMEMA及びNHS活性化POEGMEMA(NHS-POEGMEMA)ホモポリマーの合成に使用した。POEGMEMAポリマーを合成するために、DMF(3mL)中のOEGMA(600mg、2.0mmol)及びCPADB(20.12mg、0.072mmol)の溶液に、AIBN(1.31mg、0.008mmol)を添加した。混合物をN2でパージしてO2を除去し、重合を70℃で撹拌した。冷却及び空気暴露により重合を停止させた。POEGMEMAポリマーをジエチルエーテル中で沈殿させることにより精製した。ポリマー沈殿物を真空下で乾燥させて、約35のOEGMEMA繰り返し単位(460mg、収率77%)を得た。NHS-POEGMEMAホモポリマーの合成のために、連鎖移動剤としてSCPDB(27.10mg、0.072mmol)を使用して同じ手順を適用して、約35のOEGMEMA繰り返し単位(480mg、収率80%)を得た。
RAFT重合をPOEGMEMA-b-PCombMA及びNHS-POEGMEMA-b-PCombMAブロックコポリマーの合成に使用した。DMF(0.75mL)中のCombMA(100mg、0.26mmol)及びマクロ連鎖移動剤としてのPOEGMEMAポリマー(50mg、0.005mmol)の溶液に、AIBN(0.15mg、0.00092mmol)を添加した。混合物をN2でパージしてO2を除去し、重合を65℃で撹拌した。冷却及び空気暴露により重合を停止させた。粗生成物をジエチルエーテル中で沈殿させた。ポリマー沈殿物を真空乾燥して、約32のCombMA繰り返し単位(98mg、65%収率)を得た。マクロ連鎖移動剤としてNHS-POEGMEMA(50mg、0.005mmol)を使用してNHS-POEGMEMA-b-PCombMAブロックコポリマーを合成するために同じ手順を適用して、約33のCombMA繰り返し単位(105mg、収率70%)を得た。
NHS-POEGMEMA-b-PCombMA(50mg、0.002mmol)及びcRGDfK(6.4mg、0.01mmol)をDMF(0.25mL)に共溶解し、この反応混合物にN,N-ジイソプロピルエチルアミン(6.5mg、0.05mmol)を添加した。反応混合物を30℃で24時間撹拌した。粗生成物をジエチルエーテル中で沈殿させた。ポリマー沈殿物を減圧乾燥して、cRGDfK-POEGMEMA-b-CombMA(41mg、収率82%)を得た。cRGDfK-POEGMEMA-b-CombMAブロックコポリマーの調製を示す全体図を図1として提供する。
本明細書において、「標的化」とは、cRGDfK-POEGMEMA-b-CombMAブロックコポリマーからなるポリマー集合体を指し、「非標的化」とは、POEGMEMA-b-PCombMAブロックコポリマーからなるポリマー集合体を指す。
蛍光プローブ法を標的化及び非標的化集合体のCMC値の決定に利用した。ブロックコポリマー溶液(450μL)を、上記のようにバイアル中で段階希釈を使用してTHF中で調製した。THF中のナイルレッドの50μL溶液(0.03mg/mL)、次いで3mLの水を各バイアルに添加した。THFを開放雰囲気で完全に蒸発させ、3mLの水中1×10-9~1×10-5Mの範囲の16個の試料についての最終濃度値を得た。蛍光測定値を550nmの励起波長で蛍光分光光度計により記録し、発光を580~660nmでモニターした。
5-フルオロウラシル(250mg、1.92mmol)及び37%ホルマリン(244μL)を60℃で2時間反応させた。次いで、混合物を冷却し、完全に凍結乾燥して粘稠な化合物を得た。第2の工程として、この生成物(315mg、1.97mmol)を無水アセトニトリル(5.8mL)に溶解し、次いでトリエチルアミン(422μL、3.03mmol)をこの溶液に添加した。反応混合物を0℃に冷却した後、塩化メタクリロイル(232μL、2.38mmol)を滴下した。反応を室温で一晩進行させ、次いで白色沈殿物を濾別した。全ての揮発物を真空下で蒸発させ、次いで粗生成物をジクロロメタン(20mL)で溶解し、続いて1MのHCl(2×10mL)、1MのNaHCO3(10mL)、及びブライン(10mL)で抽出した。有機部分を濃縮した後、生成物を、エチルアセタート:ヘキサン混合物(30:70v/v)で溶出するシリカカラムクロマトグラフィーにより純粋な形で単離した。生成物を粘性無色油状物として得た(305mg、収率68%)。
可逆的付加-開裂連鎖移動(RAFT)重合をPOEGMEMAホモポリマーの合成に使用した。POEGMEMAポリマーの合成のために、DMF(2.5mL)中のOEGMA(500mg、1.66mmol)及びCPADB(11.97mg、42.85μmol)の溶液に、AIBN(0.78mg、4.76μmol)を添加した。混合物をN2でパージしてO2を除去し、重合を70℃で16時間撹拌した。冷却及び空気暴露により重合を停止させた。POEGMEMAポリマーをジエチルエーテル中で沈殿させることにより精製した。ポリマー沈殿物を真空乾燥して、95mgのポリマーを収率19%で得た。
RAFT重合をPOEGMEMA-b-P5FU-MAブロックコポリマーの合成に使用した。DMF(0.30mL)中の5FU-MA(17.9mg、78.6μmol)及びマクロ連鎖移動剤としてのPOEGMEMAポリマー(40mg、3.93μmol)の溶液に、AIBN(0.13mg、0.786μmol)を添加した。混合物をN2でパージし、O2を除去して重合を70℃で16時間撹拌した。冷却及び空気暴露により重合を停止させた。粗生成物をジエチルエーテル中で沈殿させた。ポリマー沈殿物を真空乾燥して、16mgのポリマーを収率28%で得た。
2-ヒドロキシエチルメタクリラート(500mg、3.8mmol)、4,4’-ジチオ酪酸(1.83g、7.6mmol)、N,N’-ジシクロヘキシルカルボジイミド(1.59mg、7.8mmol)、4-(ジメチルアミノ)ピリジン(281mg、2.3mmol)を100mL丸底フラスコ中のN2下で無水ジクロロメタン(DCM)(54mL)に溶解した。反応液を室温で16時間撹拌した。粗生成物を冷ジエチルエーテル中で沈殿させ、-20℃で20分間放置した。生成物を、エチルアセタート及びヘキサン(20:80v/v)を用いるシリカカラムクロマトグラフィーを使用することにより精製した(426mg、収率32%)。
可逆的付加-開裂連鎖移動(RAFT)重合をPOEGMEMAの合成に使用した。POEGMEMAポリマーの合成のために、DMF(5mL)中のOEGMA(1.0g、3.3mmol)及びCPADB(36.88mg、0.133mmol)の溶液に、AIBN(2.17mg、0.0013mmol)を添加した。混合物をN2でパージし、O2を除去して、重合を70℃で16時間撹拌した。冷却及び空気暴露により重合を停止させた。POEGMEMAポリマーをジエチルエーテル中で沈殿させることにより精製した。ポリマー沈殿物を真空乾燥して、715mgのポリマーを収率69%で得た。
POEGMEMA-b-PComb-SS-MAブロックコポリマーの合成には、RAFT重合を使用した。DMF(1.07mL)中のComb-SS-MA(80mg、0.20mmol)及びマクロ連鎖移動剤としてのPOEGMEMAポリマー(134mg、0.020mmol)にAIBN(0.68mg、0.004mmol)を添加した。混合物をN2でパージしてO2を除去し、重合を65℃で撹拌した。冷却及び空気暴露により重合を停止させた。粗生成物をジエチルエーテル中で沈殿させた。ポリマー沈殿物を真空乾燥して、収率65%で98mgのポリマーを得た。
配列表2 <223>配列番号2
配列表3 <223>周期
Claims (3)
- 治療薬を送達するためのブロックコポリマーの形態の式Iのポリマー-薬物コンジュゲート、
式中、
・R1、R2、及びR3は、独立して、H又は-CH3から選択される
・xは、1~100の自然数である
・yは、1~100の自然数である
・nは、1~50の自然数である
・Lは、切断可能なリンカーであるか、又はヌルであり治療薬Dがポリマー鎖にエステル、イミン、アミド、ジスルフィド、カーボナート、カルバマート又はヒドラジンを介して直接結合している
・Dは抗癌剤であり、コンブレタスタチン、又は5-フルオロウラシル(5-FU)、又はゲムシタビンである
・Aは、末端基であり、標的部分とコンジュゲーションした連鎖移動剤の断片もしくは開始剤の断片であり、該標的部分は抗体、抗体断片又はペプチドからなる群から選択される
・Bは、末端基であるか、又はBはヌルである。 - 請求項1に記載の式Iのポリマー-薬物コンジュゲートを用いて形成されたポリマー集合体(ナノ粒子又はミセル)、
式中、
・R1、R2、及びR3は、独立して、H又は-CH3から選択される
・xは、1~100の自然数である
・yは、1~100の自然数である
・nは、1~50の自然数である
・Lは、切断可能なリンカーであるか、又はLは、ヌルであり治療薬Dがポリマー鎖にエステル、イミン、アミド、ジスルフィド、カーボナート、カルバマート又はヒドラジンを介して直接結合していてもよい
・Dは抗癌剤であり、コンブレタスタチン、又は5-フルオロウラシル(5-FU)、又はゲムシタビンである
・Aは、末端基であり、標的部分とコンジュゲーションした連鎖移動剤の断片もしくは開始剤の断片であり、該標的部分は抗体、抗体断片又はペプチドからなる群から選択される
・Bは、末端基であるか、又はBは、ヌルであってもよい。 - 疎水性相互作用により式Iのポリマー-薬物コンジュゲートに結合した、カプセル化された抗癌剤を第二の抗癌剤としてさらに含む、請求項2に記載のポリマー集合体(ナノ粒子又はミセル)。
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