JP6590809B2 - カテコールで官能化された磁性ナノ粒子、その生成および使用 - Google Patents
カテコールで官能化された磁性ナノ粒子、その生成および使用 Download PDFInfo
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Description
i)FeIIIのポリオール溶液が、Fe0から出発して調製され、
ii)マグネタイトナノ粒子が、ポリオール合成条件で調製される、
調製プロセスについて記載する。
Fe0+2H+→Fe2++1/2H2↑
− 有機バインダーでコーティングされたナノ粒子の懸濁液と混合され、溶媒に溶解したポリマーの有機溶液、ただし両方は同一の溶媒である
および
− 1mMのNa2HPO4水溶液
が、バッチまたは連続合成の混合セルの中で、一定の流量で混合される。
Tリンパ球、単球、マクロファージ、樹状細胞、ナチュラルキラー細胞、Bリンパ球、好中性顆粒球、好酸性顆粒球、好塩基性顆粒球、ガンマデルタ細胞
から選択される。
腫瘍に対して用いられるTリンパ球は、標準化された方法を用いて、および/または選択的MACS(登録商標)法(カレント・プロトコル・イン・イムノロジー(Current Protocols in Immunology)2013年;デリオス(D’Elios)ら、ジャーナル・オブ・イムノロジー(J Immunol)1997年;158巻、962−967頁)を採用して、末梢血から、または関連する腫瘍抗原の事前投与後の腫瘍部位からもしくは患者のリンパ節から、または関連するとみなされるような身体の他の区域から精製される。
完全DMEM10%FBS
完全DMEM:
・DMEM高グルコース(DME/高)、(ユーロクローン(EUROCLONE))(コード:ECB7501L)
・L−グルタミン、溶液200mM(100×)、(ユーロクローン)(コード:ECB 3000D)
・ペニシリン−ストレプトマイシン溶液(100×)、(ATCC)(コード:30−2300)
・10%ウシ胎児血清FBS:ウシ胎児血清、クオリファイド(Qualified)(シグマ−アルドリッチ(Sigma−Aldrich))(コード:F6178−100mL)からなる。必要な場合には、患者の自己血清または無血清培地は、ウシ胎児血清の代わりに用いられることになる。
ジエチレングリコールDEGに含まれる酢酸鉄の調製
試薬
0.716molに等しい40gのFe(Fe<99%、<212mm)、800gの水、10.67molに等しい800gのCH3COOH(80%)、0.41molに等しい46.64gの過酸化水素水(30%)、0.12gの濃HCl、DEG(ジエチレングリコール:diethylene glycol)3850g。
鉄、酢酸水溶液、および塩酸を、窒素気流下で5000mLの4つ口フラスコに入れ、温度を90℃にし、6時間維持した。系を放置してN2下で冷却させ、溶液を濾過して未溶解Feを除去した。ドリッパを用いてフラスコに入れた透明な溶液に過酸化水素水を滴下し、1時間35℃に温度を保ち、鉄の力価として2.40w/w%を有する1628.3gに等しい透明溶液を得る。次に過剰な酸をストリッピングする。これは、40℃の温度での第1の真空蒸留、水による乾燥部の再循環、および2回の蒸留(2回連続洗浄)による除去、ならびに約50℃の温度での最後のストリッピングによって行う。理論上の鉄の力価を、1.01w/w%Feの値にするために、乾燥させたものに、3850gのDEGを添加する。
ジエチレングリコールに含まれるFe3O4ナノ粒子の調製
試薬
1.50gのFe0(Fe0<99%、<212mm)Fe0=0.179mol、150gのDEG、DEGと37%の濃HClが1:10の溶液1.2g、DEGに含まれる300.00gのFeAc3(1.01w/w%FeIII)。
有機バインダーN−(3,4ジヒドロキシフェネチル)ドデカンアミド(DDA)の調製
0.1318molに等しい25gの塩酸ドーパミン、1LのTHF、45mLのトリエチルアミン0.32mol、31.20mLの塩化ラウロイル0.135mol。
400mLのTHF(アルドリッチ(Aldrich)401757−2L−Lot STBC4923V)
935mLの酢酸エチル(アルドリッチ34972−2,5L−Lot 57BC011AV)
315mLの石油エーテル(アルドリッチ77379−2,5L−Lot BCBG7367V)。
5Lの4つ口フラスコに、窒素雰囲気下で塩酸ドーパミン次にTHF(1L)を入れ、次にトリエチルアミンを添加し、系を約20分間撹拌下に保ち、白色懸濁液を得る。
次に、合成生成物を含有する有機相を精製し、反応中に形成された副生成物から生成物を回収する。2回の再循環で(2×200mL)ロータベーパでの溶媒の除去により精製を行う。他方では、合成フラスコ中の固形残留物および残留痕跡に、分離漏斗で、水性抽出および酢酸エチルでの処理を行う。有機相を全て混ぜ合わせ、Na2SO4で乾燥させ、最後にロータベーパで乾燥させる。57gの橙色の油状生成物を得る。
生成物に、450mLの、石油エーテル:酢酸エチル=7:3の混合物を添加する。懸濁液を冷水下に置くと、白色固体が結晶化しはじめた。系を1日放置して、静置させた。
(THF中に含まれる)Fe3O4ナノ粒子の表面官能化
試薬
2.164×10−3molと等しい40.0gのFe3O4分散体、3.247×10−3molと等しい1089mgのDAA、120mLのEtOH、80.0gのTHF。
DLS
(アセトンに含まれる)Fe3O4ナノ粒子の表面官能化
試薬
0.2×10−3molと等しい4.0gのFe3O4分散体、0.3×10−3molと等しい108.0mgのDAA、12.0mLのEtOH、13.6mLのアセトン。
DLS
ポリマーPLGA−b−PEG−COOH 43−3kDaの合成
ブロックコポリマーPLGA−b−PEG−COOHの合成の場合、ジシクロヘキシルカルボジイミド(DCC:dicyclohexylcarbodiimide)のカップリング化学を用いてN−ヒドロキシスクシンイミド(NHS:N−hydroxysuccinimide)で前駆体PLGA−COOH(MW44−10kDa)を活性化し、次に、以下に記載されるように、ジクロロメタン(DCM:dichloromethane)のアミノ官能性部位のPEG−NH2(MW2−3kDa)と付加物を組み合わせた。
工程1:NHSでのカルボキシ基(carboxylic)官能性の活性化
98g PLGA−COOH(50:50 ポリ(DL−ラクチド−コ−グリコリド))、カルボキシレート末端基
1.037g NHS(N−ヒドロキシスクシンイミド 98%)
720mL DCM(ジクロロメタン>99.9%)
1.98g DCC(N,Nジシクロヘキシルカルボジイミド 99%)
990mL DCM(ジクロロメタン>99.9%)
1600mL ジエチルエーテル(≧99.8)。
窒素下の5Lの4つ口フラスコにPLGA−COOHおよび600mLのジクロロメタンを添加した。ポリマーの可溶化後、N−ヒドロキシスクシンイミド(NHS)、次に、N,Nジシクロヘキシルカルボジイミド(DCC、一度に約0.25g)を添加して、不活性雰囲気中で約40時間、系を撹拌しながら放置した。原料を失わないために、120mLのジクロロメタンを用いて、漏斗の固体を洗浄した。
CH2Cl2−PM=119.38
DIPEA N−エチルジイソプロピルアミン [(CH3)2CH]2NC2H5−PM=129.24
COOH−PEG−NH2 HClxNH2−PEG−O−C3H6−COOH−PM PEG=3000da
PLGA−NHS(反応中間体)
1L(合成) CHCl3(クロロホルム≧99.5)
100mL+250mL(洗浄) CHCl3(クロロホルム≧99%、0.75%のエタノールで安定化)
1.2mL DIPEA(N,N−ジイソプロピルエチルアミン 99.5%)
7g COOH−PEG−NH2(ポリマー−塩酸塩形態比)
1250mL ジエチルエーテル(≧99.8%)
1250mL 脱イオン水。
窒素気流下の機械的撹拌機が装着された2Lの3つ口フラスコにおいて、結果として生じた中間体を1Lのクロロホルムに溶解させた。シリンジを用いて系に1.2mLのDIPEAを添加し、続いて7gのCOOH−PEG−NH2を添加した(少量添加)。約90時間不活性気流下で、系を撹拌しながら放置した。
合成(PLGA−b−PEG−COOH 12−3kDa)
工程1:NHSでのカルボキシ基(carboxylic)官能性の活性化
試薬
7gのPLGA−COOH 7000〜17000(50:50 ポリ(DL−ラクチド−コ−グリコリド)、カルボキシレート末端基)→0.582mmol
PLGA−COOHの可溶化のための150mLのCH2Cl2(ジクロロメタン−>99.9%)
30mLのCH2Cl2で洗浄された0.27gのNHS(N−ヒドロキシスクシンイミド−98%)→2.34mmol
50mLのCH2Cl2で洗浄された0.51gのDCC(N,Nジシクロヘキシルカルボジイミド−99%)→2.493mmol
ブフナー漏斗(Buckner)で濾過する前に500mLのフラスコを洗浄するための70mLのCH2Cl2(ジクロロメタン>99.9%)
550mLのジエチルエーテル(アルドリッチ≧99.8%)。
粘度の高い懸濁液に含まれるPLGA−NHS(反応中間体)
中間体のための260mLのCHCl3(クロロホルム−アルドリッチ≧99.5%−触媒)
アミノPEG COOHの洗浄のための20mLのCHCl3
0.35mLのDIPEA(N,N−ジイソプロピルエチルアミン 99.5%)
1.82gのCOOH−PEG−NH2(ポリマー−塩酸塩形態比)→0.6066mmol
520mLのジエチルエーテル(≧99.8%)
300mLの脱イオン水。
窒素下の500mLのフラスコに、中間体100(×2)および60mLのCHCl3を可溶化した。シリンジを用いて系に0.35mLのDIPEAを添加し、続いて20mLの漏斗洗浄CHCl3と1.82gのCOOH−PEG−NH2を添加した。96時間不活性気流下で、系を撹拌しながら放置した。
(2g) P.M.:11300g/mol−0.1769mmol
(5g) P.M.:15400g/mol−0.3246mmol
mmol PLGA COOH:
0.5015gのPLGA PEG COOH(mol2g*P.M.2g)+(mol5g*P.M.5g)=2.529+5.972=8.5g
PM=12000で計算。8.74gのPLGA PEG COOHが予想される。
ナノバイオリアクタ(NBR)のセットアップ
試薬
9.5e−04molのFe3O4に等しい40.0gのFe3O4−DDA、5e−06molのポリマーに等しい220.0mgのPLGA−b−PEG−COOH、400mlのリン酸緩衝液1mM。
DLS
DMEM+10%FBS+グルタミン+抗生物質で、1:20(0.05wt%の無機相)まで試料を希釈する。それはアグリゲートのない透明である。
連続ナノバイオリアクタ生成(NBR)
試薬:
4.4e−06molのポリマーと等しい200mgのPLGA−b−PEG−COOH、52.6gのTHF、8.6e−04molのFe3O4と等しい36.4gのFe3O4−DDA、pH7.4のリン酸緩衝液を有するH2O MilliQ1000mL=10−3M。
水流への有機溶液の添加を実施するために、較正後にダブル蠕動ポンプシステムをセットアップした(THF/水容積比=1/10)。それぞれのチューブは、(PLGA−b−PEG−COOHおよび粒子を有する)THF溶液ならびに2.5Lのボトルで調製されたリン酸緩衝溶液を含有する人工心肺装置から直接溶液を引き出す。
理論上の濃縮係数:4.7×
理論上の濃度:0.078%
濃縮および透析に必要とされる時間:20分。
回収量:11.51g膜内部の正味のデッドボリューム約1〜2mL。
(Vdead1.5mLを考慮する)理論上の濃度:14%。
DLS
moAbで標的化されたナノバイオリアクタ(NBR_hERG)のセットアップ
試薬
0.533μmolの−COOHと等しい40.38mLのNBR、0.533μmolに等しい0.23mMのスルホ−NHS溶液2.32mL、0.053mmolに等しい28mMのEDAC*HCl溶液190μL、4.0mgのhERG(2.7e−08mol)と等しい1.52mg/mLのhERG溶液2.64mL、1500mLのNa2HPO3水溶液=10−3M。
DLS
BCA試験の実行のために、対応する抗体不含(NBR)の濃度に関して、NBR_hERGの濃度を正規化し、従って、ブランク(white)として機能する。染色が関連する試薬の添加により進行すると、UV−可視分光光度計で試料を分析し、次に(BSA標準を用いて)予め作製された較正曲線上で吸光度値を補間し、同等のmoAb濃度を外挿する。NBR_hERGの試料に相当するものから、溶出液中およびブランク(white)(NBR)中に見つかったmoAbの値を差し引くことにより、NBR_hERGに存在する抗体の正味の量を計算する。以下の等式を参照のこと。
CmoAb(NBR_moAb)net=CmoAb(NBR_moAb)−CmoAb(NBR)−CmoAb(eluate)
mAb溶出液=45μg/mL
mAb NBR=435μg/mL
mAb NBR_hERG=863μg/mL
実際のmAb(mAb NBR_hERG−mAb NBR)=428μg/mL
比率mAb/Fe3O4=0.14。
フルオ染料で標的化されたナノバイオリアクタ(NBR_Fluo)のセットアップ
試薬技術仕様
NBR [Fe3O4]=0.081% [PLGA−b−PEG−COOH]=0.061%*
1,4−ジアミノブタン MW=88.15g/mol d=0.877g/mL
Alexa Fluor(登録商標)750(750nm) MW=1300g/mol
水でメスアップしたリン酸緩衝液 C=1M、pH7.4。
30.00mLのNBR(0.40μmolのPPGC43−3.1)
1mgのAlexa Fluor 750(770μL中→[1mM])
7.4のリン酸緩衝液を含むH2O MilliQ1500mL=10−3M
スルホ−NHS MW=217.13g/mol
EDAC・HCl MW=191.7g/mol。
770μLのDMSOでフルオロフォアを可溶化し、溶液1nmol/μLを得る。12mLのバイアル瓶に、1mMのリン酸緩衝液4950μLを添加し、50μLのフルオロフォアAlexa Fluor 750溶液(50nmol)を加える。次に、それを磁気撹拌下に置き、次に132μg/mLの1,4−ジアミノブタン溶液100μL(150nmolに相当するもの=13.2g)を添加する。溶液を放置して、暗闇中および窒素気流下で、24時間反応させる。後続の精製なしの合成工程のために、このように得られたNH2−末端フルオロフォアを用いることになる。
5.0mgのスルホ−NHSを、正確に計量し、1mMのリン酸緩衝液を用いて100mLのフラスコ中で可溶化する。
4mLのバイアル瓶に、2.7mgのEDACおよび1mMの緩衝液0.5mLを添加する。混合を容易にするために、ふたをして振盪する。本溶液は、反応の直前に調製しなければならない。
100mLの容器に、30.00mLのNBR DFを添加し、0.14mLのEDAC(0.028M)および1.72mLのスルホ−NHS(0.23mM)を添加する。
ペリコンXLの500kDaのPES膜およびイージーロードIIヘッド(easy−load II head)を備えた蠕動ポンプマスターフレックス(Masterflex)L/Sを用いて、生成物を透析するためにシステムをセットアップする。次に、システムを滅菌して、0.5%の次亜塩素酸ナトリウムを溶かし放置して約30分間反応させる。無菌MilliQ水で洗浄し、1mMのリン酸緩衝液(同じく無菌)でシステムをセットアップした後、生成物を10mLの容積まで濃縮して(23mlの透過物を収集)、ポンプ速度を約12mL/min(P=0.25mbar)に設定する。最初の透過物の速度は、UV−可視分析のために保持する。次に、12mL/min(P=0.25mbar)の速度で動作する、1mMの緩衝液40mL(4容積)でそれを透析する。この時点で、6mLの容積までそれを濃縮する。
理論上の合成濃縮係数:5.8×
NBRと比較した理論上の濃縮係数:5×
0.22μMのマイレクス(Millex)のPESフィルタで、生成物を濾過する。全生成物を精製する場合、1つのフィルタが必要とされる。冷蔵庫でそれを保存する。
回収されたNBR_27_Fluo_01 DF=4.49g。
DLS
R0366/2013;R0368/2013
R0368/2013
R0368/2013
R0368/2013
フルオ染料で標的化されたナノバイオリアクタ(NBR_Fluo)のセットアップ
試薬技術仕様
NBR [Fe3O4]=0.081% [PPGC43−3.1]=0.061%*
1,4−ジアミノブタン MW=88.15g/mol d=0.877g/mL
Alexa Fluor 750(750nm) MW=1300g/mol
水でメスアップしたリン酸緩衝液 C=1M、pH7.4。
30.00mLのNBR(0.40μmolのPPGC43−3.1)
50.00nmolのシアニン5−1,4−ジアミノブタン (5.0mL中→[10μM])
7.4のリン酸緩衝液を含むH2O MilliQ1500mL=10−3M
スルホ−NHS MW=217.13g/mol
EDAC・HCl MW=191.7g/mol。
12mLのバイアル瓶に、1mMのリン酸緩衝液5mL、50nmol(1ボトル)のシアニン5、NHS−エステル、および次に150nmol(13.2g)の1,4−ジアミノブタンを添加する。溶液を放置して、暗闇中、磁気撹拌下、および窒素気流下で、24時間反応させる。後続の精製なしの合成工程のために、このように得られたNH2−末端フルオロフォアを用いることになる。
5.0mgのスルホ−NHSを、正確に計量し、1mMのリン酸緩衝液を用いて100mLのフラスコ中で可溶化する。
4mLのバイアル瓶に、2.7mgのEDACおよび1mMの緩衝液0.5mLを添加する。混合を容易にするために、ふたをして振盪する。本溶液は、反応の直前に調製しなければならない。
50mLの無菌容器に、30.00mLのNBRを添加し、0.14mLのEDAC(0.028M)および1.72mLのスルホ−NHS(0.23mM)を添加する。
ペリコンXLの500kDaのPES膜を用いて、生成物の透析のためにシステムをセットアップする。
理論上の合成濃縮係数:5.5×
NBRと比較した理論上の濃縮係数:4.8×
0.22μMのマイレクスのPESフィルタで、生成物を濾過する。全生成物を精製する場合、1つのフィルタが必要とされる。冷蔵庫でそれを保存する。
回収されたNBR_Fluo=4.11g。
moAbおよびフルオ染料で標的化されたナノバイオリアクタ(NBR_hERG−Fluo)の生成
試薬技術仕様
NBR [Fe3O4]=0.821% [PPGC43−3.1]=0.616%
1,4−ジアミノブタン MW=88.15g/mol d=0.877g/mL
シアニン5−NHSエステル (650nm)
水でメスアップしたリン酸緩衝液 C=1M、pH7.4
スルホ−NHS MW=217.13g/mol
EDAC・HCl MW=191.7g/mol
hERG1 MW=15000g/mol。
4.79mLのNBR (0.64μmolのPPGC43−3.1)
25nmolのシアニン5−NHSエステル (2.5mL中→[10μM])
2.7mgのEDAC
5.0mgのスルホ−NHS
4.8mgのhERG (3.2mL→1500μg/ml)
pH7.4のリン酸緩衝液を有するH2O MilliQ1500mL []=10−3M。
12mLのバイアル瓶に、1mMのリン酸緩衝液5mL、50nmol(1ボトル)のシアニン5NHS−エステルを添加し、磁気撹拌下に置き、次に13.2mg/100mLの1,4−ジアミノブタン溶液100μLを添加する(150nmolに相当するもの=13.2μg)。溶液を放置して、暗闇中および窒素気流下で、24時間反応させる。後続の精製なしの合成工程のために、このように得られたNH2−末端フルオロフォアを用いることになる。
5.0mgのスルホ−NHSを、正確に計量し、1mMのリン酸緩衝液を用いて100mLのフラスコ中で可溶化する。
4mLのバイアル瓶に、2.7mgのEDACおよび1mMの緩衝液0.5mLを添加する。混合を容易にするために、ふたをして振盪する。本溶液は、反応の直前に調製しなければならない。
無菌の100mLの容器に、1mMの緩衝液7.95mL、次に4.79mLのNBRを添加する。混合物を穏やかに撹拌して混合し、次に2.29mLのEDAC(0.028M)および2.79mLのスルホ−NHS(0.23mM)を添加する。
NBR_19にすでに用いられているペリコンXLの500kDaのPES膜を用いて、生成物を透析するためにシステムをセットアップする。300mLのH2O MilliQで洗浄し、次に0.5%の次亜塩素酸ナトリウム400mLで溶かし、約30分間次亜塩素酸塩中に放置する。1mMの緩衝液400mLでシステムを洗浄する。
NBRと比較した理論上の希釈係数:1.3×
0.22μMのマイレクスのPESフィルタで、生成物を濾過する。全生成物を精製する場合、1つのフィルタが必要とされる。冷蔵庫でそれを保存する。
回収されたNBR_hERG−Fluo=7.79g。
DLS
活性成分が付加されたナノバイオリアクタ(NBR_PTXおよびNBR_hERG_PTX)の生成
試薬技術仕様
PPGC43−3.1(バッチ5−A) 50:50 Mw=43000、PEG Mw3000
Fe3O4−DDA [Fe3O4]=0.55%
PTX ディスカバリー・ファイン・ケミカル(Discovery Fine Chemicals)
1mMのリン酸緩衝液 pH=7.4
THF d=0.89。
35.6gのFe3O4−DDA(40.0mL)(195.8mgのFe3O4) 490mg/L(水中)
212.6mgのPPGC43−3.1 490mg/L(水中)
21.2mgのPTX
1mMのリン酸緩衝液400ml(実際:440mL)
25Gの針の60mLのシリンジ。
4mLのTHF(4mLのバイアル瓶)に212.6mgのPPGC43−3.1を可溶化させ、2.12mLのTHF(4mLのバイアル瓶)に21.2mgのPTXを可溶化させ、100mLのフラスコ内の35.6gのFe3O4−DDAにこれを添加する。
25Gの針を備えた60mlのシリンジを用いて、1mMのリン酸緩衝液400mlに、THF溶液をスタックする。
得られたNBR_PTX:455.8g。
存在するTHFを除去するために、ロータベーパで生成物を処理する。この目的のために、1000mLのフラスコにそれを移し、次の条件に設定する。
恒温槽 温度40℃
圧力:154mbar
回転:80rpm。
ロータバップで回収されたNBR_PTX=418.22g(37.58gのTHFが除去された)。
次の手順に従って、50kDaの膜を備えるAMICONシステムで、生成物を濃縮および透析する。
1)50mLの逆浸透水(osmotized H2O)で洗浄して、膜中の不純物を除去する。
2)50mLの水で10−3Mにメスアップしたリン酸緩衝水溶液を含む溶液でのシステムの洗浄。
理論上の濃縮係数=7.7×
ミリポアステリベクス 0.22μMのPESフィルタ(円筒形フィルタ)で生成物を濾過する。
DLS
DMEM+10%のFBS+グルタミン+抗生物質で1:8に希釈された濃縮試料は、アグリゲートがなく澄んでいる。
R0211/2013
活性成分が付加されたナノバイオリアクタ(NBR_PTXおよびNBR_hERG_PTX)の生成
試薬技術仕様
NBR_PTX [Fe3O4]=0.48% [PPGC43−3.1]=0.36%*
水でメスアップしたリン酸緩衝液 C=1M、pH7.4
スルホ−NHS MW=217.13g/mol
EDAC MW=155.24g/mol d=0.877g/mL
hERG MW=150000g/mol。
4.26mLのNBR_PTX_p10 DF (3.33*10−4μmol PPGC43−3.1)
5.0mgのスルホ−NHS (100mL中→[0.23mM])
20μLのEDAC (4mL中→[28mM])
2.5mgのhERG (0.833mL*3mg/mL)
pH7.4のリン酸緩衝液1500mL []=10−3M。
5.0mgのスルホ−NHSを計量し、1mMのリン酸緩衝液を用いて、100mLのフラスコ中で可溶化する。
4mLのバイアル瓶に、2.7mgのEDACおよび1mMの緩衝液0.5mLを添加する。混合を容易にするために、ふたをして振盪する。本溶液は、反応の直前に調製しなければならない。
無菌の40mLの容器に、1mMの緩衝液2.36mL、次に4.26mLのNBR_PTXを添加する。混合物を穏やかに撹拌して混合し、次に1.19mLのEDAC(0.028M)および1.45mLのスルホ−NHSを添加する。
全容積:2.36mL+4.26mL+1.19mL+1.45mL=9.26mL
ペリコンXLの500kDaのPES膜を用いて、生成物の透析のためにシステムをセットアップする。300mLのH2O MilliQで洗浄し、次に0.5%の次亜塩素酸ナトリウム400mLで溶かし、約30分間次亜塩素酸塩中に放置する。1mMの緩衝液400mLでシステムを洗浄する。
理論上の合成濃縮係数:5.5×
NBR_PTXと比較した理論上の希釈係数:2.8×
0.22μmのステリベクスのPESフィルタで生成物を濾過する。全生成物を精製する場合、1つのフィルタが必要とされる。冷蔵庫でそれを保存する。
回収されたNBR_PTX=6.88g。
DLS
リンパ球へのNBRの組み込み
T細胞およびジャーカット細胞は、本出願人らにより開発された方法でナノ粒子を組み込むことができる。適切な特定の培養培地(培地)中で0.05%の濃度のNPを、T細胞/ジャーカット細胞に付加する。NPを含有する培地を形成するために、はじめにNPを、次に特定の培地を分散する。次の通り、培地を作製する。
・RPMI 1640培地、w2.0g/LのNaHCO3−w/o L−グルタミン、(バイオクロム(BIOCHROM))(コード:F1215)−500mL、以下のものを添加される
・L−グルタミン、溶液200mM(100×)、(ユーロクローン)(コード:ECB 3000D)−希釈なしの5.5mL
・ピルビン酸ナトリウム、100mM(100×)、(ギブコ(Gibco))(コード:11360−039)−希釈なしの5.5mL
・MEM NEAA 最小必須培地 非必須アミノ酸(100×)、(ギブコ)(コード:11140−035)−希釈なしの5.5mL
・GENTOMIL(ゲンタマイシン)80mg/2ml(AIC N°029314059)−12mLのバイアル瓶
・2−メルカプトエタノール(メルク(Merck))(コード:444203)−次の通り、5.5mLの2−メルカプトエタノールを用いる。99.963mLの無菌H2Oに溶かした37μlの2−メルカプトエタノール(最終容積100mL)
・10%のウシ胎児血清FBS:ウシ胎児血清、クオリファイド(シグマ−アルドリッチ)(コード:F6178)。
Claims (17)
- 複数の磁性ナノ粒子を含む構造体であって、前記磁性ナノ粒子の表面がカテコールで官能化され、前記磁性ナノ粒子は、ナノメートルのマグネタイト粒子からなり、かつ官能化された前記複数の磁性ナノ粒子がクラスタを形成する、生体適合性のポリマーマトリックス中に封入されるものである、構造体。
- 治療作用を有する分子が前記生体適合性のポリマーマトリックス中に分散される、請求項1に記載の構造体。
- 複数の金ナノロッドをさらに含む、請求項1または2に記載の構造体。
- 前記生体適合性のポリマーマトリックスが生分解性ポリマーおよびコポリマーからなる、請求項1〜3のいずれか1項に記載の構造体。
- 前記生分解性ポリマーおよびコポリマーが、ポリエステル、ポリウレタン、ポリカーボネート、ポリグルタミン酸、ポリエーテルアミン、およびポリベンジルグルタメートから選択される、請求項4に記載の構造体。
- 前記生分解性コポリマーが、乳酸−グリコール酸コポリマーおよびポリエチレングリコールカルボキシレート(PLGA−b−PEG−COOH)からなり、式(I)を有し、
- 治療作用を有する前記分子が、抗癌剤、過酸化亜硝酸捕捉剤、スーパーオキシドジスムターゼ阻害剤、レチノイド、サイトカイン、アスピリンから選択される、請求項2に記載の構造体。
- 前記コポリマーのフラグメントPEG−COOHの末端カルボキシ基が、モノクローナル抗体、タンパク質、ペプチド、または細胞過剰発現による特異的認識のために目的の活性分子でさらに官能化される、請求項6に記載の構造体。
- 前記抗体が、hEGR、hEGFR、IgG、moAbから選択される、請求項8に記載の構造体。
- 有機バインダーでコーティングされたナノ粒子の懸濁液と混合され、溶媒に溶解したポリマーの有機溶液であって、両方が同一の溶媒である有機溶液、
および
Na2HPO4水溶液1mM
が、バッチまたは連続合成の混合セルの中で、一定の流量で混合される、請求項1〜6のいずれか1項に記載の構造体を調製するためのプロセス。 - フラグメントPEG−COOHの末端カルボキシ基が、アミノ末端基のエステル化による後続の攻撃を促進するために活性化される、請求項8に記載の構造体を調製するためのプロセス。
- 請求項1〜8のいずれか1項に記載の構造体を含有する、ヒト免疫系の細胞。
- 前記ヒト免疫系の細胞が、Tリンパ球、単球、マクロファージ、樹状細胞、ナチュラルキラー細胞、Bリンパ球、好中性顆粒球、好酸性顆粒球、好塩基性顆粒球、ガンマデルタ細胞から選択される、請求項12に記載の細胞。
- 温熱療法のための前記構造体を付加したヒト免疫系の細胞の製造のための、請求項1〜9のいずれか1項に記載の構造体の使用。
- 癌、変性疾患、中枢神経系疾患、脳心血管疾患、感染症、移植関連疾患、自己免疫疾患の診断のための、ならびに、さらに腫瘍、脳心血管疾患、変性疾患(例えば、アルツハイマー病)、感染症、移植関連疾患、肝硬変、および線維形成を特徴とする他の疾患、習慣性流産、子宮内胎児死亡を特徴とする疾患、新生児疾患、先天性および後天性凝固障害、遺伝障害、自己免疫疾患の処置のための、ならびに、疼痛緩和に使用するための、請求項12または13に記載の細胞。
- MRI撮像手段として有用であるための前記構造体を付加したヒト免疫系の細胞の製造のための、請求項1〜9のいずれか1項に記載の構造体の使用。
- 腫瘍疾患の診断および処置のための前記構造体を付加したヒト免疫系の細胞の製造のための、請求項3に記載の構造体の使用。
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