JP2017515839A - 合成脳浸透遺伝子ベクターの操作 - Google Patents
合成脳浸透遺伝子ベクターの操作 Download PDFInfo
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Abstract
Description
本出願は、2014年5月12日に出願された米国特許出願第61/991,898号、2014年5月12日に出願された米国特許出願第61/991,920号および2014年5月22日に出願された米国特許出願第62/001,994号の優先権および利益を請求し、その開示は、参照によって本明細書により明示的に援用される。
本発明は、米国国立衛生研究所によりJustin Hanesに授与された助成金番号EB003558および助成金番号CA164789のもと政府の支援によりなされた。政府は、本発明における特定の権利を有する。
用語「生体適合性」は、本明細書において使用される場合、それ自体が宿主(例えば、動物またはヒト)に対し有毒でもなければ、宿主において毒性濃度のモノマーもしくはオリゴマーサブユニットまたは他の副産物を産生する速度で分解(ポリマーが分解する場合)もしない、1または複数の材料を指す。
II.組成物
A.ナノ粒子
1.コーティング剤
i.ポリエチレングリコール(PEG)
iii.コーティング剤の密度
2.コアポリマー
i.ポリマーの種類
ii.分岐状ポリマー
iii.コポリマー
3.核酸
・ 正常遺伝子をゲノム内の非特異的位置に挿入して、非機能的遺伝子を置き換えることができる。このアプローチが最も一般的である。
・ 異常遺伝子を、相同組換えにより正常遺伝子に取り替えることができる。
・ 異常遺伝子をその正常機能に戻す選択的復帰変異により、該異常遺伝子を修復することができる。
・ 特定の遺伝子の調節(遺伝子がオンまたはオフされる程度)を変更することができる。
4.追加的な活性薬剤
5.ナノ粒子特性
i.粒子拡散率
ii.界面動電位
iii.粒子サイズ
iv.毒性
B.脳への送達のための医薬賦形剤
II.製造方法
A.ポリマー調製
B.ナノ粒子
1.溶媒蒸発
2.溶媒除去
3.噴霧乾燥
4.転相
III.使用方法
A.治療上の使用
1.処置しようとする障害または疾患
B.投与および投薬方法
1.対流増強送達
2.投与レジメ
(実施例1)
カチオン性ポリマーに基づく遺伝子ベクターに固有の正の表面電荷を遮蔽するためのベクターの調製
材料と方法
ポリマー調製
遺伝子ベクター複合体形成
ナノ粒子の物理化学的特徴付け
結果
(実施例2)
遺伝子ベクター粒子は、生理的環境におけるインキュベーション後に安定的である
材料と方法
結果
(実施例3)
遺伝子ベクター粒子は、in vitroおよびin vivoで無毒性である
材料と方法
細胞培養
in vitro毒性
結果
(実施例4)
ペグ化ナノ粒子遺伝子ベクターは、高い取り込みおよびトランスフェクション効率を有する
材料と方法
in vitroトランスフェクション
結果
(実施例5)
BPNペグ化ナノ粒子遺伝子ベクターは、脳実質に急速に浸透した
材料と方法
動物試験
齧歯類脳スライスにおける多重粒子追跡
イメージングおよび解析
統計解析
結果
(実施例6)
CEDは、遺伝子ベクター物理化学的特性とともに、高密度に(dencely)ペグ化された遺伝子ベクターの分布および導入遺伝子送達を増強するように働く
材料と方法
イメージングおよび解析
抗体およびウエスタンブロッティング
結果
(実施例7)
ポリL−リシンおよび分岐状PEGを含有するナノ粒子の合成
材料と方法
分岐状PEG(BrPEG)の合成
ポリ−L−リシンのペグ化
ペグ化ペプチドの精製および対イオンの交換
粒子製剤
結果
ポリマー合成
粒子特徴付け
(実施例8)
in vitroにおけるポリL−リシンおよび分岐状PEGを含有するナノ粒子の特徴付け
材料と方法
細胞培養
細胞取り込み
ルシフェラーゼアッセイ
毒性アッセイ
結果
毒性
細胞取り込み
トランスフェクション
(実施例9)
ポリL−リシンおよび分岐状PEGを含有するナノ粒子は、ex vivoおよびin vivoで脳組織における高い拡散率を有する
材料と方法
aCSFにおける粒子安定性
齧歯類脳スライスの調製
多重粒子追跡
in vivo共注射
結果
aCSFにおける粒子安定性
粒子拡散
in vivo共注射
Claims (26)
- 脳を含む組織への核酸の送達のためのナノ粒子製剤であって、
核酸と、
第1の親水性カチオン性ポリマーと、
ポリエチレングリコール、ポリエチレンオキシドおよびこれらのコポリマーからなる群から選択される第2の親水性中性電荷直鎖状または分岐状ポリマーと
を含み、
該カチオン性ポリマーの90%〜75%が、該親水性ポリマーにコンジュゲートされ、または該カチオン性ポリマーの少なくとも50%が、分岐状親水性ポリマーにコンジュゲートされており、該核酸が、該ナノ粒子内に被包され、もしくは該ナノ粒子の表面に会合しており、該ナノ粒子が、ほぼ中性の電荷を付与し、該組織にわたる拡散率を増強する密度の該親水性ポリマーでコーティングされているナノ粒子製剤。 - 前記脳実質内への送達のための、請求項1に記載のナノ粒子製剤。
- 114nm、100nmまたは50nm未満のあるいは114nm、100nmまたは50nmに等しい直径を有する、請求項1に記載のナノ粒子製剤。
- 前記第1のカチオン性ポリマーまたは第2の中性電荷親水性ポリマーが、分岐している、請求項1に記載のナノ粒子製剤。
- 前記第2の親水性ポリマーが、1,000ダルトン〜10,000ダルトンの間の分子量を有するポリエチレングリコールである、請求項1に記載のナノ粒子製剤。
- 前記ポリエチレングリコールが、5,000ダルトンの分子量を有する、請求項5に記載のナノ粒子製剤。
- 前記第1のカチオン性ポリマーが、10,000ダルトン〜50,000ダルトンの間の分子量を有する分岐状ポリエチレンイミンである、請求項1に記載のナノ粒子製剤。
- 第1のカチオン性ポリマーに対する第2の中性電荷親水性ポリマーのモル比が、8を超える、請求項7に記載のナノ粒子製剤。
- ポリマーに対する核酸のN対P比が、少なくとも2である、請求項8に記載のナノ粒子製剤。
- 前記第1のカチオン性ポリマーが、ポリ−Lリシンである、請求項1に記載のナノ粒子製剤。
- 前記第2の中性電荷親水性ポリマーが、5,000ダルトンの個々の分岐の分子量を有する分岐状ポリエチレングリコールである、請求項10に記載のナノ粒子製剤。
- 前記ポリ−Lリシンの少なくとも50%が、ポリエチレングリコールにコンジュゲートされている、請求項11に記載のナノ粒子製剤。
- 前記第2の中性電荷親水性ポリマーの質量が、前記粒子の質量の少なくとも1/10,000、1/7500、1/5000、1/4000、1/3400、1/2500、1/2000、1/1500、1/1000、1/500、1/250、1/200、1/150、1/100、1/75、1/50、1/25、1/20、1/5、1/2または9/10である、請求項1に記載のナノ粒子製剤。
- 総ナノ粒子と比べた前記第2の親水性ポリマーの重量パーセントが、少なくとも80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%またはそれ超である、請求項1に記載のナノ粒子製剤。
- 前記ナノ粒子が、マンニトールのような浸透圧媒体において製剤化されて、前記脳内への取り込みを増強する、請求項1に記載のナノ粒子製剤。
- 前記脳への治療剤の送達のための投薬製剤であって、
該脳への投与のための請求項1〜15のいずれか一項に記載の治療有効量のナノ粒子、および
該脳内への送達のための薬学的に許容される賦形剤
からなる製剤。 - 前記ナノ粒子が、対流増強送達を使用した前記脳への直接的投与のために製剤化されている、請求項16に記載の製剤。
- 前記ナノ粒子が、前記脳への全身性または鼻腔内投与のために製剤化されている、請求項16に記載の製剤。
- 前記ナノ粒子が、少なくとも10分間、20分間、30分間、1時間、2時間、4時間(hour hours)、6時間、10時間、1日間、3日間、7日間、10日間、2週間、1ヶ月間またはそれより長い期間にわたって、有効量の前記核酸を放出する、請求項16に記載の製剤。
- 前記脳への核酸の送達のための、親水性ポリマーで高密度にコーティングされたナノ粒子を作製する方法であって、
第1のカチオン性親水性ポリマーを、第2の中性電荷親水性ポリマーにコンジュゲートされた該第1のポリマーと混合することにより、ブレンドされたポリマーを調製するステップと、
該ブレンドされたポリマーに該核酸を添加するステップと、
該ナノ粒子を精製して、請求項1〜15のいずれか一項に記載のナノ粒子を生成するステップと
を含む方法。 - 前記脳の疾患または障害の1または複数の症状を処置するための方法であって、
請求項1〜19のいずれか一項に記載の治療有効量のナノ粒子製剤
を含む製剤を該脳に投与するステップを含む方法。 - 前記製剤が、前記脳へと直接的に投与される、請求項21に記載の方法。
- 前記製剤が、全身性または鼻腔内に(intransally)投与される、請求項21に記載の方法。
- 前記粒子が、該粒子の血液脳関門の通過を容易にするための1または複数の技法と組み合わせて投与される、請求項21に記載の方法。
- 前記技法が、局所注射、直接的植え込み、対流増強送達、電子常磁性共鳴、マイクロバブルを伴うまたは伴わない超音波処理および浸透圧剤の使用からなる群から選択される、請求項24に記載の方法。
- 前記疾患または障害が、腫瘍、神経学的障害および脳傷害または外傷からなる群から選択される、請求項21に記載の方法。
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