JP2018533543A - シリカ系生体分子担体、それを含む医薬組成物、その作製方法、及びその使用 - Google Patents
シリカ系生体分子担体、それを含む医薬組成物、その作製方法、及びその使用 Download PDFInfo
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Abstract
Description
C16TABr(0.58g、1.64×10−3モル)とテトラエトキシシランの0.226Mエタノール溶液(TEOS、20mLの99.5%エタノール中1mLのTEOS)5mLを、300gの0.17Mアンモニア水溶液に溶解した。ストック溶液を40℃で5時間撹拌した。TEOSの1.13Mエタノール溶液(20mLの99.5%エタノール中、5mLのTEOS)5mL及びFITC−APTMSを1時間に亘って勢いよく撹拌しながら添加した後、40℃で24時間に亘り静的にエイジングさせた。室温で24時間に亘って5mLエタノール(99%)中、フルオレセインイソチオシアネート(FITC、1mg)及び3−アミノプロピルトリメトキシシラン(APTMS、100μL)を撹拌することによってFITC−APTMS、N−1−(3−トリメトキシシリルプロピル)−N’−フルオレシルチオウレア(fluoreceylthiourea)を予め用意した。その後、合成されたままの試料を12000rpmで20分間、遠心分離によって収集し、99%エタノールで5回洗浄した。200mgの合成されたままの試料を37重量%のHCl 0.5gを含む25mLの95%エタノールに再度分散した。60℃で24時間に亘ってエタノール懸濁液を加熱することにより界面活性剤を抽出した。FITC−MSNと呼ばれる生成物を遠心分離によって収集し、エタノールで数回洗浄してエタノール中に保存した。
APTMSによる処理でアミン基によってMSNの表面を官能基化した。MSN(200mg)を最初に50mLのエタノールに分散し、その後、500μLのAPTMSを添加した後、該溶液を18時間還流した。遠心分離及びエタノールによる洗浄の後、アミン官能基化MSNをエタノールに再度分散させた。界面活性剤を除去するため、アミン官能基化MSNを酸性エタノール(50mLのEtOH中の1gのHCl)に懸濁し、24時間還流した。遠心分離及びエタノールによる洗浄の後、アミン官能基化MSN(MSN−APTMS)をエタノールに再度分散させた。
75kVの動作電圧でHitachi H−7100測定器を使用してTEM画像を得た。試料を超音波処理してエタノール中に分散し、10μLの懸濁液を滴下してマイクログリッド上に固定した。
WST−1アッセイを適用して、細胞の生存率及び増殖阻害アッセイを測定した:HeLa細胞生存率アッセイのため、1ウェル当たり2×104個のHeLa細胞を24ウェルプレートに16時間に亘って蒔いた。HeLa細胞を種々の量のMSN−PEG3.4k−Ab−TAT(100μg/mL)を含む血清不含培地中で4時間インキュベートした。頭頸部扁平上皮癌(HNSCC)増殖阻害アッセイのため、HNSCC細胞を4×104細胞/ウェルの密度で24ウェルプレートに16時間に亘って蒔き、200μg/mLのMSN−PEG3.4k−Ab(1:24)−TAT、MSN−PEG3.4k−TAT又は抗TNF抗体(100ng/mL)と共に血清不含培地中で4時間インキュベートした。培養培地で培地交換をした後、HNSCC細胞を更に72時間インキュベートした。WST−1アッセイのため、HeLa細胞又はHNSCC細胞をWST−1(Clontech)を含む培養培地中、37℃で4時間生育させた。生きている細胞によって生成される暗赤色のホルマザン色素は生きている細胞数に比例し、450nmでの吸光度をマイクロプレートリーダー(Bio-Rad、モデル680)を使用して測定した。
細胞溶解物を10%SDS−PAGE上で分離した後、タンパク質をポリビニリデンジフルオリド(PVDF)メンブレンに電気泳動的に転写させ、ブロッキングバッファー[1×Tris−緩衝生理食塩水(TBS)−0.1% Tween 20、5重量/容積%の脱脂粉乳]中、室温で1時間ブロッキングした。メンブレンを、Cayman(米国ミズーリ州アナーバーのCayman)製のCOX−2と共に、一次抗体:Santa Cruz Biotechnology(カリフォルニア州サンタクルーズ)製のNF−κB p65、TNF−α、ラミンB、及びGAPDHと4℃で一晩インキュベートした。全ての一次抗体をブロッキングバッファーに希釈した(NF−κB p65:1:500、TNF−α:1:500、ラミンB:1:3500、GAPDH:1:5000、及びCOX−2:1:500の希釈)。PVDFメンブレンを広範囲に洗浄し、室温で1時間に亘ってホースラディッシュペルオキシダーゼ複合化二次免疫グロブリンG抗体(1:2000希釈、Santa Cruz Biotechnology)と共にインキュベートした。製造業者のプロトコルに従って、増強化学発光基質キット(英国バッキンガムシャーのGE Healthcare UK LtdのAmersham Pharmacia Biotech)により免疫反応性のバンドを可視化した。
100μg/mLのMSN−APTMS、MSN−PEG2k及びMSN−PEG3.4kを4時間に亘ってHeLa細胞において処理した後、NF−κB活性化因子であるTNF−α(50ng/mL)を含まずに、又はそれらと共に更に0.5時間インキュベートした。細胞を採取した後、細胞質タンパク質及び核タンパク質を単離し、細胞質ゾル又は核のいずれかのp65発現レベルをウエスタンブロット実験によって特定した。in vitroプルダウンアッセイのため、MSN−PEG3.4k−Ab−TAT(100μg/mL)をHeLa細胞の全溶解物と混合し、4℃で18時間に亘ってin vitroでインキュベートした。その後、該混合物を20分間に亘って12000rpmで遠心分離し、ウェスタンブロッティングにより遊離p65発現レベルについて上清(10μL)をアッセイした。
色素−官能基化MSNを同時縮合プロセスによって合成した。5mlの無水エタノール中に1mgのFITCを溶解することによってFITC溶液を用意した。室温で暗闇の中24時間に亘って急速撹拌しながら100μLのAPTMSを添加した。0.58gのC16TABを0.17MのNH3溶液300gに溶解し、5mLの希釈TEOS溶液(5容積/容積% TEOS/エタノール)を5時間に亘って撹拌しながら添加した。FITC−APTMS溶液を添加した後、5mlの濃縮TEOS溶液(25容積/容積% TEOS/エタノール)を1時間に亘って勢いよく撹拌しながら滴加した。その後、該溶液を40℃で24時間に亘ってエイジングし、シリカ縮合を完了した。合成されたままの生成物を遠心分離によって収集し、95%エタノールで3回洗浄した。FITC−MSN(FMSN)と呼ばれる生成物を無水エタノール中に保存した。
100mgのFMSNを50mgのNTA−シランを含有する50mLのトルエン中に懸濁し、18時間還流した。生成物をエタノールによって浄化して、過剰なシランを排除した。C16TABrテンプレートを除去するため、粒子を酸性溶液(50mLのエタノール中1gのHCl)に分散して、60℃で24時間撹拌した。その後、65℃で6時間に亘って撹拌しながら、水性ρ−TsOH(0.266g、pH=2.0)の存在下でNTAリンカー上のメトキシカルボニルの加水分解を達成した。エタノールによって浄化した後、粒子を50mMのNiCl2水溶液と室温で6時間反応させた。上に記載されるものと同じ浄化手順に従って、FMSN−NTA−Niを得て、無水エタノール中に保存した。Ni含有量の平均負荷を伴うFMSN−NTA−Niは、ICP−MS分析により0.6重量%であった。
色素−官能基化MSNを同時縮合プロセスによって合成した。5mLの無水エタノール中に1mgのFITCを溶解することによってFITC溶液を用意した。室温で暗闇の中24時間に亘って急速撹拌しながら100μLのAPTMSを添加した。0.58gのC16TABを0.17MのNH3溶液300gに溶解し、5mLの希釈TEOS溶液(5容積/容積% TEOS/エタノール)を5時間に亘って撹拌しながら添加した。FITC−APTMS溶液を添加した後、5mLの濃縮TEOS溶液(25容積/容積% TEOS/エタノール)を1時間に亘って勢いよく撹拌しながら滴加した。900μLのPEG−シラン及び40μLのPEI−シランを添加し、30分間撹拌した。その後、該溶液を40℃で24時間エイジングしてシリカ縮合を完了した。該溶液を90℃で24時間及び70℃で24時間に亘って熱水条件下でエイジングした。合成されたままの生成物を遠心分離によって収集し、95%エタノールで洗浄した。粒子を1gの37重量%HClを含む95%エタノール50mL中に1時間に亘って再度分散させた後、酸性溶液を50μLの37重量%HClを含む95%エタノール50mLに変更してCTABを除去した。FITC複合化MSN(FMSN)−PEG/PEI粒子を遠心分離によって収集し、95%エタノールで3回洗浄した。
120kVで作動するJEOL JSM−1200 EX II上で透過型電子顕微鏡(TEM)画像を得た。試料のニッケル量を、Agilent 7700e測定器を使用して誘導結合プラズマ質量分析(ICP−MS)によって特定した。Malvern Zetasizer Nano ZS(英国、Malvern)上で動的光散乱(DLS)を使用してサイズ測定を行った。電気泳動度の後、Malvern Zetasizer Nano ZS(英国、Malvern)に対してヘンリーの式(Henry equation)を適用することにより、ゼータ電位を特定した。表1は、種々の溶液中のFMSN−PEG/PEIナノ粒子の平均粒径に対する動的光散乱(DLS)データを示す。
20mgのFMSN−PEG/PEIを2.5mLのPBSバッファーに分散した後、6.8mgのNHS−PEG−MAL(3.4k)を2.5mLのPBSに溶解し、その後、FMSN−PEG/PEI溶液に添加した。該溶液を室温で2時間撹拌した。5mLのPBSバッファーに400μLのトラウト試薬(Traut's reagent)(100μM)及び5.24mgのNα,Nα−ビス(カルボキシメチル)−L−リジン水和物を添加し、30分間撹拌することにより、チオール化Nα,Nα−ビス(カルボキシメチル)−L−リジン水和物(BCLH)溶液を用意した。チオール化BCLH溶液をFMSN−PEG/PEI溶液に添加し、4℃で一晩撹拌した。その後、65℃で6時間に亘って撹拌しながら、水性ρ−TsOH(0.133g、pH=2)の存在下でNTAリンカー上のメトキシカルボニルの加水分解を達成した。エタノールによって洗浄した後、粒子を50mMのNiCl2水溶液と室温で6時間反応させた。上に記載されるものと同じ洗浄手順に従って、FMSN−PEG/PEI−NTA−Niを得て、無水エタノール中に保存した。
His−TAT−SOD又はHis−TAT−GPxを含むE.コリ溶解物を4℃で一晩、FMSN−NTA−Niと混合した。Ni(II)と非常に低い解離定数を有する緊密な結合を提供するHis−タグタンパク質との間の金属親和性に基づき、精製せずに8M尿素の下、E.コリの粗溶解物のペレット上清に由来するTAT−SOD又はTAT−GPxタンパク質とFMSN−NTA−Niを直接混合した。タンパク質複合化粒子を遠心分離によって単離し、エタノールで洗浄した。タンパク質−官能化粒子をFMSN−TAT−SOD又はFMSN−TAT−GPxとして表示する。
SODの場合、試料を300μLで用意し、マイクロプレートリーダー(Bio Tek、Synergy(商標)H1)を使用してモニターした。最初に、1mLの50mM K3PO4にEDTA(10−4M)、シトクロムc(10−5M)及びキサンチン(5×10−5M)を含むカクテル試薬のストックを用意した。その後、280μLのカクテル試薬に様々な試料、キサンチンオキシダーゼ(58mU/mLを10μL)を添加し、最大300μLの全容積の脱イオン水で完了した。最後に、200μLの各試料をマイクロプレートリーダーに移し、550nmでの吸光度を検出した。SOD活性を測定するため、天然のSODとSOD試料との間のシトクロムc還元の阻害率をt=0秒とt=180秒との間の吸光度の勾配を使用して比較した。SOD比活性は、全溶解物タンパク質1ミリグラム当たりの単位(U/mg)として表される(The Journal of Biological Chemistry, 1969, 244, 6049-6055.)。
増殖アッセイのため、1ウェル当たり3×104細胞を24ウェルプレートに蒔いた。血清不含培地に懸濁された種々の量のナノ粒子と共にそれぞれ4時間インキュベートした後、その後、500μMのN,N’−ジメチル−4,4’−ビピリジニウムジクロリド(パラコート)を24時間に亘って培養培地に添加した。その後、粒子処理細胞をPBSで2回洗浄し、DMEM中のWST−1(10%)200μLと共にインキュベートした。生きている細胞によって生成されるホルマザン色素によって細胞生存率を推定し、450nmの吸光度をマイクロプレートリーダー(Bio-Rad、モデル680)を使用して測定した。
Claims (19)
- シリカ系生体分子担体であって、
多孔質コアと、
第1の生理活性部分と、
前記第1の生理活性部分と機能的に関連する第2の生理活性部分と、
前記第1の生理活性部分及び前記第2の生理活性部分を、前記多孔質コアにそれぞれ複合化させるためのリンカーと、
を含む、シリカ系生体分子担体。 - 前記第1の生理活性部分が、酵素、抗体、触媒模倣物、リガンド、ホルモン、生体分子結合タンパク質、及びそれらの機能性フラグメントからなる群から選択される、請求項1に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分が転写因子抗体であり、前記第2の生理活性部分がオルガネラターゲッティング生体分子又は細胞透過性生体分子である、請求項1に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分及び前記第2の生理活性部分が、カスケード反応に関与する異なる酵素又は酵素フラグメントである、請求項1に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分及び前記第2の生理活性部分が、活性酸素種代謝に関与する異なる酵素又は酵素フラグメントである、請求項4に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分及び前記第2の生理活性部分が変性形態である、又は部分的に活性形態である、請求項4に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分及び前記第2の生理活性部分の少なくとも一方が細胞透過性ドメインを含む、請求項1に記載のシリカ系生体分子担体。
- 前記第1の生理活性部分及び前記第2の生理活性部分の少なくとも一方がポリヒスチジンタグを含む、請求項1に記載のシリカ系生体分子担体。
- 前記リンカーの少なくとも1つがポリエチレングリコールセグメントを含む、請求項1に記載のシリカ系生体分子担体。
- 前記リンカーの少なくとも1つが二価のニッケルイオン又はコバルトイオンを含む、請求項1に記載のシリカ系生体分子担体。
- 前記リンカーの少なくとも1つが、共有結合を介して、前記第1の生理活性部分、前記前記第2の生理活性部分、又はそれらの両方に結合される、請求項1に記載のシリカ系生体分子担体。
- 前記リンカーの少なくとも1つが、前記多孔質コアに連結した第1の末端と、前記第1又は第2の生理活性部分に連結した第2の末端と、細胞取込みを促進するための前記第1の末端と前記第2の末端との間の機能的セグメントとを含む、請求項1に記載のシリカ系生体分子担体。
- 前記多孔質コアが、ポリエチレンイミン、アミノ基、ニトリロ三酢酸、ポリエチレングリコール、蛍光タグ、又はそれらの組み合わせによって官能基化される、請求項1に記載のシリカ系生体分子担体。
- 前記多孔質コアが2nm〜50nmの平均孔径を有する、請求項1に記載のシリカ系生体分子担体。
- 前記多孔質コアが300nm未満の粒径を有する、請求項1に記載のシリカ系生体分子担体。
- 生物学的媒質中に分散された、請求項1〜15のいずれか一項に記載のシリカ系生体分子担体を複数含む医薬組成物。
- 組成物を作製する方法であって、
多孔質コアを有するシリカ系担体を準備することと、
前記多孔質コア上にリンカーを形成することと、
前記リンカーの少なくとも一部を介して第1の生体分子を前記多孔質コアに複合化させることと、
前記リンカーの少なくとも一部を介して前記第1の生体分子と機能的に関連する第2の生体分子を前記多孔質コアに複合化させることと、
を含む、方法。 - 細胞障害に関連する疾患又は状態の治療に対する医薬の製造において、請求項1〜15のいずれか一項に記載のシリカ系生体分子担体を含む組成物を使用する方法。
- 前記疾患又は状態が、酵素欠損症、酵素欠乏、癌、及び代謝障害からなる群から選択される、請求項18に記載の方法。
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