JP2017524791A - 活性薬剤の送達のための両親媒性ブロックコポリマー - Google Patents
活性薬剤の送達のための両親媒性ブロックコポリマー Download PDFInfo
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- JP2017524791A JP2017524791A JP2017508049A JP2017508049A JP2017524791A JP 2017524791 A JP2017524791 A JP 2017524791A JP 2017508049 A JP2017508049 A JP 2017508049A JP 2017508049 A JP2017508049 A JP 2017508049A JP 2017524791 A JP2017524791 A JP 2017524791A
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Abstract
Description
マクロ開始剤としてmPEG2−ABCPAおよびモノマーとしてHPMAm−Bzを用いて、コポリマーポリ(エチレングリコール)−b−(N−(2−ベンゾイルオキシプロピル)メタクリルアミド))(mPEG−b−p(HPMAm−Bz))を合成した。モノマーは、Y.Shiらによる、Biomacromolecules 2013, 14, 1826−1837に記載された手順に従って合成された。フェニル基はエステルリンカーを介してHPMAモノマーに結合する。マクロ開始剤の合成は、D.Neradovicらによる、Macromolecules, 2001, 34(22), 7589〜7591頁に記載されている。
空のmPEG−b−p(HPMAm−Bz)ミセルは次のように調製した。mPEG−b−p(HPMAm−Bz)を27mg /mLの濃度でTHFに溶解し、続いて1mLの逆浸透(RO)水に1mLのポリマー溶液を攪拌しながら滴下した。混合物を室温で48時間インキュベートしてTHFを蒸発させた。得られたミセル分散液を0.45μmのナイロン膜(Acrodisc(登録商標))で濾過した。
ヒトA431腫瘍異種移植片は、100μLのPBS pH 7.4に懸濁した1×106のA431細胞を用いてマウスの右脇腹に皮下接種することによって確立した。腫瘍はデジタルキャリパーを用いて測定した。腫瘍体積V(mm3)は、式V=(π/6)LS2を用いて計算した。ここで、Lは最大、Sは最小の表面直径である。腫瘍が80〜100mm3の体積に達したとき、マウスを研究に含めた。マウスに尾静脈を介して100μLのPTX負荷ミセル(3.2mg/mLのPTXおよび27mg/mLのポリマー)を注射した。
この実施例では、フルオロフォア標識Cy7およびCy5.5を使用して、PTX負荷ミセルの動態特性をインビボで研究する。Cy7はポリマー鎖に共有結合し、注入されたミセルの最終結果を知らしめる。 Cy5.5は、ミセルのコアに物理的に負荷され、モデル薬剤として使用された。
実施例4と同様に、MDA−MB−468乳癌異種移植片を有するマウスにおいて、PTX負荷mPEG−b−p(HPMAm−Bz)ミセルの治療効果を調べた。この研究では、マウスはA431研究(実施例4)と同様の処置を受けたが、静脈内注射は1日おきに投与するのではなく、1週間に1回投与した。腫瘍細胞を接種してから4週間後、腫瘍が約100mm3の体積に達したとき、処置を開始した。
デキサメタゾン、ドキソルビシン塩酸塩(DOX.HCl)、ベダキリン、DAPTおよびシクロスポリンAのうちの異なる薬剤をカプセル化するために、カプセル化手順に従った。使用されたポリマーは、バッチ番号J01(Mn48.000,[モノマー]/[開始剤]=600/1)およびJ02(Mn59.000,[モノマー]/[開始剤]=1000/1)を有するmPEG−b−p(HPMAm−Bz)、およびmPEG−bp(HPMAm−Nt)250(Mn32.000,[モノマー]/[開始剤]=250/1)であるJ03である。分子量MnはNMRにより測定する。活性剤の化学式を図9に示す。
ポリマー5mgと薬剤/薬剤候補1mgを溶解したテトラヒドロフラン1mLを、逆浸透水(RO)1mLに攪拌しながら滴下し、さらに1分間攪拌を続けた。混合物を一晩フュームフードに入れ、テトラヒドロフランを蒸発させた。薬剤負荷ミセル分散液(dox製剤を除く)を0.45μmの膜で濾過し、濾液をDLSで分析(形成されたミセルの大きさ)し、アセトニトリルに溶解した(1容量のミセル分散液を19容量のアセトニトリルに加えた)。これにより、UV−可視分光法によるカプセル化効率(EE)および負荷容量(LC)の測定を行った(HPCLによって分析されたパクリタキセルを除くすべての薬剤)。DOX.HClを負荷したミセルの場合、製剤をvivaspin管を用いて10000gで5分間遠心分離し、濾液中の非負荷薬剤をUV−可視分光法によって定量してEEおよびLCを計算した。結果を表1に示す。
1−[2−(2−ベンゾイルヒドラゾノ)プロピルアミノ] −2−メチル−2−プロペン−1−オン(BHMPO)の合成
180℃で一晩乾燥したフラスコに、1−(アセトニルアミノ)−2−メチル−2−プロペン−1−オン(AMPO、677mg、4.8mmol)および4−メトキシフェノール(重合禁止剤、6mg; 0.05mmol)を窒素雰囲気下、室温で、146mLのメタノール(A4モレキュラーシーブ上で乾燥)に溶解した。AMPOは、ACS Biomater, Sci. Eng, 2015, 1(6), 393〜404頁に記載の方法に従って合成した。 この溶液にBH(626mg、4.6mmol)を加えた。5分間撹拌した後、7.5mLの氷酢酸を溶液に添加し、反応物を窒素雰囲気下で室温で24時間撹拌し続けた。溶媒を減圧下で除去し、粗生成物をヘキサン/酢酸エチル(1/9、v/v)の溶出液を用いるシリカカラムクロマトグラフィー(40g)により精製した。Rfが0.4の化合物(ヘキサン/酢酸エチル(1/1、v/ v))を含む画分を集め、溶媒を減圧下で除去した。最終生成物を収量834mg(71%)の黄色粉末として回収し、示差走査熱量測定(Discovery、TA Instruments)によって測定した融点は164℃であった。DMSO−d6を溶媒として用い、Gemini 300MHz分光計(Varian Associates Inc. NMR Instruments、Palo Alto、CA)を使用して1H NMR分析により構造を確認した。 2.52ppmのDMSOピークを基準線として使用した。化学シフト(DMSO−d6):11.3(s,C=N−NH−CO)、8.7(t,CO−NH−CH2)、7.9(d,2H, 芳香族CH)、7.5(m,3H,芳香族CH)、5.7および5.4(s,CH2=C)、4.0(d,NH−CH2−C)、2.0(s,CH3−C=C)、1.9(s,CH2−C(CH3)=N)。
マクロ開始剤としてmPEG2−ABCPAを、モノマーとしてBHMPOを用いて、マクロ開始剤経路を介してmPEG−b−p(BHMPO)のブロックコポリマーを合成した。モノマーをDMSO(A4モレキュラーシーブ上で乾燥)中に0.3g/mLの濃度で溶解し、モノマー対マクロ開始剤のモル比は200/1であった。溶液を窒素で30分間フラッシングすることにより脱気した。反応は、窒素雰囲気下、70℃で24時間行った。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、この溶解/沈殿操作を2回繰り返した。ポリマーを真空下、室温で24時間乾燥させ、淡黄色の粉末として回収した。
以下のようにして、パクリタキセル(PTX)を負荷したmPEG−b−p(BHMPO)(23kDa、NMRによる;図10に示す構造)ミセルを調製した:THF / MeOH(=テトラヒドロフラン/メタノール)(1/1、v/v)中のPTX(4mg)およびポリマー(27mg)の溶液1mLを攪拌しながらRO水1mlに滴下し、10μLのリン酸塩緩衝液pH7.4(1M)を混合物に添加して、pHを7.4に調整した。ミセル分散液を室温で24時間インキュベートして、有機溶媒を蒸発させた。次に、ミセル分散液を0.45μmの膜を通して濾過した。動的光散乱分析を用いて形成されたミセルのサイズを測定し、PTX負荷をHPLCによって測定した。PTX濃度は、3.3mg/ml、カプセル化効率は(EE)83%、粒子サイズは83nm、PDIは0.08であると測定された。
空のmPEG−b−p(BHMPO)ミセルは、PTXを添加せずに、上記の方法を用いて調製した。ミセル分散液のpHを、pH5.0の150mM酢酸アンモニウム緩衝液またはpH6.5のNaH2PO4緩衝液中で5回希釈することによって、それぞれ5.0または6.5に調整した。異なるpH値および37℃での空のmPEG−b−p(BHMPO)ミセルのpH依存安定性を、DLSを用いてミセルのサイズおよび光散乱強度をモニターすることによって研究した。結果を図11に示す。
Claims (15)
- 少なくとも1つの親水性ブロックおよび少なくとも1つの疎水性ブロックを含むブロックコポリマーであって、前記疎水性ブロックは、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、ビニルエーテルおよびそれらの芳香族誘導体からなる群から選択され、前記少なくとも1つの疎水性ブロックは芳香族側基を含み、当該芳香族側基は前記疎水性ブロックに分解性リンカーで結合されており、前記芳香族側基はアリールである、ブロックコポリマー。
- 前記アリール基はフェニルまたはナフチルである、請求項1に記載のコポリマー。
- 前記疎水性ブロックは、2−ヒドロキシエチルメタクリレート、2−ヒドロキシエチルアクリレート、グリセリルメタクリレート、グリシジルメタクリレート、グリセリルアクリレート、グリシジルアクリレート、ヒドロキシプロピルメタクリルアミドからなるリストから選択されるモノマーを含む、請求項1または2に記載のコポリマー。
- 前記疎水性ブロックは、ヒドロキシアルキルメタクリルアミドを含む、請求項1または2に記載のコポリマー。
- 前記親水性ブロックはポリアルキレングリコール、より好ましくはポリエチレングリコールを含む、上述の請求項のいずれか一項に記載のコポリマー。
- 前記分解性リンカーは、エステル、オルトエステル、アミド、カーボネート、カルバメート、無水物、ケタール、アセタール、ヒドラゾンおよびそれらの誘導体から選択される、上述の請求項のいずれか一項に記載のコポリマー。
- 前記分解性リンカーは、エステルリンカーまたはヒドラゾンリンカーである、請求項6に記載のコポリマー。
- 前記疎水性ブロックのモノマーの25モル%超が前記芳香族側基を含有する、上述の請求項のいずれか一項に記載のコポリマー。
- 上述の請求項のいずれか一項に記載のブロックコポリマーおよび少なくとも1つの物理的に封入された活性成分を含む制御放出系。
- 前記ポリマーは疎水性コアを有する高分子ミセルの形態であり、前記活性成分は前記ミセルの前記疎水性コアに物理的に封入されている、請求項9に記載の制御放出系。
- 前記活性成分は疎水性または両親媒性である、請求項9または10に記載の制御放出系。
- 前記活性成分は治療薬または診断薬である、請求項9乃至11のいずれか1項に記載の制御放出系。
- 前記活性成分は、デキサメタゾン、DAPT、ドキソルビシン、イマチニブ、ベダキリン、シクロスポリンA、パクリタキセルからなるリストから選択される、請求項9乃至12のいずれか1項に記載の制御放出系。
- 2つの活性成分を含み、前記2つの活性成分は、2つの治療薬であるか、または、治療薬および診断薬である、請求項9乃至13のいずれか1項に記載の制御放出系。
- 前記活性成分はパクリタキセルである、請求項13に記載の制御放出系。
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NL2013317A NL2013317B1 (en) | 2014-08-11 | 2014-08-11 | Amphiphilic block copolymers for delivery of active agents. |
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PCT/NL2015/050574 WO2016024861A1 (en) | 2014-08-11 | 2015-08-11 | Amphiphilic block copolymers for delivery of active agents |
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KR20240055119A (ko) | 2021-09-15 | 2024-04-26 | 젤메딕스, 인크. | Gelma 중합체 조성물 및 이의 용도 |
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WO2010053597A2 (en) * | 2008-11-06 | 2010-05-14 | University Of Washington/////////////////////-+ | Micelles of hydrophilically shielded membrane-destabilizing copolymers |
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ES2391187B1 (es) * | 2011-04-26 | 2013-10-18 | Consejo Superior De Investigaciones Científicas (Csic) | Compuestos poliméricos bioactivos nanoestructurados derivados de fármacos antiinflamatorios no esteroideos (aine) e imidazol. |
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JP2005514500A (ja) * | 2001-12-31 | 2005-05-19 | ポリセリックス リミテッド | ブロックコポリマー |
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WO2016024861A1 (en) | 2016-02-18 |
CN107106693B (zh) | 2021-08-24 |
AU2015302410A1 (en) | 2017-03-09 |
CA2957900C (en) | 2023-06-13 |
CN107106693A (zh) | 2017-08-29 |
JP6837962B2 (ja) | 2021-03-03 |
US20170231908A1 (en) | 2017-08-17 |
US11007148B2 (en) | 2021-05-18 |
NL2013317B1 (en) | 2016-09-21 |
AU2015302410B2 (en) | 2019-01-17 |
EP3191534A1 (en) | 2017-07-19 |
CA2957900A1 (en) | 2016-02-18 |
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