JP4538666B2 - 薬物内包アクティブターゲット型高分子ミセル、医薬組成物 - Google Patents
薬物内包アクティブターゲット型高分子ミセル、医薬組成物 Download PDFInfo
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Description
ただし、R1は標的結合部位を有する化合物であり、R2は水酸基を末端に有してもよい炭素数1〜12の範囲にあるアルキル基であり、L1はO(CH2)pNHであり、L2はO(CH2)p−CO−であり、pは1〜5の範囲にある整数であり、Rは水素原子または疎水性有機基であり、qは1または2であり、n1およびn2は互いに独立して40〜450の範囲にある整数であり、m1およびm2は互いに独立して20〜80の範囲にある整数であり、R3は総数m2の少なくとも10〜70%が連結基を有していてもよい薬物の残基であり、存在する場合の残りの基が水素原子または疎水性有機基である。
標的結合部位を有する化合物としてトランスフェリンを有し、薬物としてカンプトテシン(CPT)を内包する高分子ミセルである、トランスフェリン結合カンプトテシンミセルを、次のようにして形成した。
薬物としてドセタキセル(DTX)を使用することによって、骨格ポリマーユニットβをドセタキセルコンジュゲート(PEG−pGlu−DTX)としたこと以外は、実施例1と同様にして、標的結合部位を有する化合物としてトランスフェリンを有し、薬物としてドセタキセルを内包する高分子ミセルである、トランスフェリン結合ドセタキセルミセルを形成した。なお、骨格ポリマーユニットαおよび骨格ポリマーユニットβのブロック共重合体部分を構成するPEGの鎖長は、いずれも10kDaにした。PEG−pGlu−DTXは、ドセタキセルがPEG−pGluにエステル結合を介して結合した状態(MeO−PEG−pGlu−DTX)にあり、上記一般式II−aで表示される構造を有する。
標的結合部位を有する化合物として上皮成長因子(EGF)を有し、薬物としてドセタキセル(DTX)を内包する高分子ミセルである、EGF結合ドセタキセルミセルを、次のようにして形成した。
標的結合部位を有する化合物として坑RANKL抗体を有し、薬物としてエベロリムス(EVE)を内包する高分子ミセルである、坑RANKL抗体結合エベロリムスミセルを、次のようにして形成した。
標的結合部位を有する化合物としてトランスフェリンを有し、薬物としてエベロリムス(EVE)を内包する高分子ミセルである、トランスフェリン結合エベロリムスミセルを、次のようにして形成した。
標的結合部位を有する化合物を有さず薬物としてドセタキセルを内包する高分子ミセル(以降、説明を容易にするために、Tf非結合DTXミセルと呼ぶ)を、次のようにして形成した。実施例2で形成したPEG−pGlu−DTXを10mg、サンプルバイアルに精秤し、20mMのリン酸ナトリウム緩衝液(pH7.0)を1mL添加して懸濁した。4℃で一昼夜撹拌した後、バイオディスラプター(日本精機製作所製High Power Unit)を用いて、氷冷下で10分間超音波処理し、孔径0.22μmのフィルター[ミリポア社製Millex(R)GP PES]でろ過し、ろ液を回収した。このろ液をゲルろ過(GEサイエンス社製PD−10、溶離液:10%スクロース溶液)することによって、Tf非結合DTXミセルを含有する高分子画分を得た。
標的結合部位を有する化合物を有さず薬物としてカンプトテシンを内包する高分子ミセル(以降、説明を容易にするために、Tf非結合CPTミセルと呼ぶ)を、次のようにして形成した。実施例1で形成したPEG−pGlu−CPTを10mg、サンプルバイアルに精秤し、精製水を1mL添加して懸濁した。4℃で一昼夜撹拌した後、バイオディスラプター(日本精機製作所製High Power Unit)を用いて、氷冷下で10分間超音波処理し、孔径0.22μmのフィルター[ミリポア社製Millex(R)GP PES]でろ過し、ろ液を回収した。そのろ液をゲルろ過(GEサイエンス社製PD−10、溶離液:20mMリン酸ナトリウム緩衝液(pH7.0))することによって、Tf非結合CPTミセルを含有する高分子画分を得た。
標的結合部位を有する化合物としてTfを有する一方、薬物を内包しない高分子ミセル(以降、説明を容易にするために、Tf結合エンプティーミセルと呼ぶ)を、次のようにして形成した。
実施例2のTf結合DTXミセルによる細胞障害性を、比較例1のTf非結合DTXミセルによる細胞障害性と比較した。各ミセルによる細胞障害性を、DSファーマバイオメディカル株式会社を介してECACC(European Collection of Cell Culture)から購入したヒト乳癌MDA−MB−231細胞を用い、WST法に基づき次のように評価した。
細胞障害性試験2では、サンプル液を添加して実施する培養時間を72時間に変更し、その直後にWST Reagentを1ウェルあたり10μLづつ添加し、37℃、5%CO2の雰囲気下で約2時間培養を続けたこと以外は、細胞障害試験1と同様にして、実施例2のTf結合DTXミセルと比較例1のTf非結合DTXミセルによる細胞障害性を調べた。
細胞障害性試験3では、細胞として、住商ファーマインターナショナル株式会社を介してATCC(American Type Culture Collection)から購入したヒト前立腺癌DU145細胞を用い、ミセルとして、実施例1のTf結合CPTミセルと、比較例2のTf非結合CPTミセルとを用い、サンプル液を添加して実施する培養時間を8時間に変更したこと以外は、細胞障害試験1と同様にして、各ミセルによる細胞障害性を調べた。
細胞障害性試験4では、細胞として、DSファーマバイオメディカル株式会社を介してECACCから購入したヒト肝癌HepG2細胞を用いたこと以外は、細胞障害試験3と同様にして、各ミセルによる細胞障害性を調べた。
細胞障害性試験5では、細胞としてヒト乳癌MDA−MB−231細胞を用いたこと以外は、細胞障害試験3と同様にして、各ミセルによる細胞障害性を調べた。
a)CPT濃度の測定方法
ミセルサンプル100μLに対し、6NのHClを200μL添加し、クライオチューブ(家田化学)にて100℃で1時間加熱した。得られた反応液を75μL回収し、6NのNaOHを50μL添加して中和した後、0.22μmフィルター(ミリポア社製MILLEX(R)−GV)でろ過した。ろ液を25mMのギ酸アンモニウム緩衝液(pH3.0)で10倍希釈し、この処理サンプル液をHPLCサンプルバイアルに充填し、下記の分析条件でHPLC分析することによって、CPT濃度を測定した。
b)HPLC分析条件
システム:Waters Alliance System
カラム:Tosoh TSK−gel ODS−80TM(4.6φ×150mm)(40℃)
移動相:25mMのギ酸アンモニウム(pH3.0)/アセトニトリル=70/30
流速:1mL/min
検出:蛍光(Ex:370nm,Em:420nm)
インジェクション体積:20μL
細胞障害性試験6では、細胞として、DSファーマバイオメディカル株式会社を介してECACCから購入したヒト乳癌MDA−MB−231細胞を用い、ミセルとして、比較例3のTf結合エンプティーミセルを用いたこと、及び薬剤と細胞の接触時間を72時間に延長する以外は、細胞障害試験3と同様にして、各ミセルによる細胞障害性を調べた。
ヒト乳癌MDA−MB−231細胞を、RPMI1640と10%FBSとから形成した培地を用い、37℃、5%CO2の雰囲気下で、移植に必要な細胞数に増殖するまで培養した。その後、この細胞を、100μLの生理食塩水に懸濁した状態で、雌性ヌードマウス[Balb nu/nu、5週齢、日本チャールス・リバー株式会社製]の背部皮下に接種した。1匹当たりに接種した細胞は3×106個である。その後、21日間ヌードマウスを飼育することによって、腫瘍体積が70.8±3.7mm3(Average±SE)になったところで、薬物内包ミセルの投与を開始した。
(1)コントロール(無処理)
(2)比較例1のTf非結合DTXミセル(1回あたりのDTXの投与量:マウスの体重1kgあたり10mg)
(3)実施例2のTf結合DTXミセル(1回あたりのDTXの投与量:マウスの体重1kgあたり10mg)
Claims (4)
- 親水性ポリマーセグメント、疎水性ポリマーセグメント、および該親水性ポリマーセグメントに結合した標的結合部位を有する骨格ポリマーユニットαと、親水性ポリマーセグメント、疎水性ポリマーセグメント、および該疎水性ポリマーセグメントに結合した薬物を有し、かつ前記標的結合部位を有さない骨格ポリマーユニットβとを含み、前記骨格ポリマーユニットαおよび骨格ポリマーユニットβが、前記標的結合部位を外側に向けると共に前記薬物を内側に向けた状態で放射状に配列しており、
i)前記放射状の配列を維持した状態で標的に結合した場合、エンドサイトーシスによって当該標的を供給する細胞の内部に取り込まれ、前記細胞内において前記放射状の配列が崩壊することによって前記薬物が当該細胞内に放出され、
ii)標的への結合以前に血中において前記放射状の配列が崩壊した場合、代謝により前記骨格ポリマーユニットβが体外に排出されることによって、前記薬物が正常細胞に損傷を与え得ることが防止された、
薬物内包アクティブターゲット型高分子ミセル。 - 前記骨格ポリマーユニットαおよびβの親水性ポリマーセグメントがそれぞれポリエチレングリコール鎖であり、疎水性ポリマーセグメントがそれぞれポリアミノ酸鎖である、請求項1に記載の高分子ミセル。
- 前記骨格ポリマーユニットαが下記一般式I−aまたは一般式I−bで表示され、前記骨格ポリマーユニットβが下記一般式II−aまたは一般式II−bで表示される、請求項2に記載の高分子ミセル。
- 請求項1に記載の高分子ミセルと、製薬学的に許容される担体とを含む医薬組成物。
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