JPWO2012153493A1 - 赤外域光による光線力学的治療又は診断剤 - Google Patents
赤外域光による光線力学的治療又は診断剤 Download PDFInfo
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Abstract
Description
1,3−ジフェニルイソベンゾフラン(DPBF)を用いて一重項酸素1O2の発生を検出した。
アルミホイルで遮光したビーカーに100mlのジメチルスルホキシド(DMSO)、DPBF2.8mg(1×10−4M)、PPIX2.0mg(2×10−5M)を入れ撹拌した。そこから25mlを別の遮光したバイアルに移し、市販のLNP(Shanghai Keyan Phosphor Technology Co. Ltd.製「Up-Conversion Anti-Counterfreit Phosphor (Green)」)250mgを入れ、半導体レーザにより980nmのNIR(出力400mA)を50mm上方から照射した。照射始めを0minとして、撹拌しながら0,3,5,7,10,15,20minのサンプルを500μl取り、1.5mlエッペンドルフチューブに移して10000rpmで5min遠心した。遠心後の上清40μlをDMSO560μlで15倍に希釈し、415nmの吸光度を測定した(LNP(+),NIR(+))。残った75mlのサンプルでコントロール実験を行った。ネガティブコントロール実験としてNIRを照射しない場合(LNP(+),NIR(−))、LNPが存在しない場合(LNP(−),NIR(+))を行い、ポジティブコントロールとして、PPIXを励起できることが知られている400nmのUVを照射するという条件(UV(+),LNP(−))で同様の実験を行った。結果を図1に示す。
実施例1と同様に、DPBFを用いて一重項酸素1O2の発生を検出した。
アルミホイルで遮光したビーカーに100mlのジメチルスルホキシド(DMSO)、DPBF2.8mg(1×10−4M)、PPIX3.6mg(3.6×10−5M)を入れ撹拌した。そこから25mlを別の遮光したバイアルに移し、市販のLNP62.5mgを入れ、半導体レーザにより980nmのNIR(出力400mA)を50mm上方から照射した。照射始めを0minとして、撹拌しながら0,1,2,3,6,8,10,15minのサンプルを500μl取り、1.5mlエッペンドルフチューブに移して10000rpmで5min遠心した。遠心後の上清40μlをDMSO560μlで15倍に希釈し、415nmの吸光度を測定した(LNP(+),NIR(+))。残った75mlのサンプルでコントロール実験を行った。ネガティブコントロール実験として、NIRを照射せず、LNPも存在しない場合(LNP(−),NIR(−))、NIRを照射しない場合(LNP(+),NIR(−))、LNPが存在しない場合(LNP(−),NIR(+))で同様の実験を行った。結果を図2に示す。
ヒト胃がん由来細胞株であるMKN45細胞をLNP存在下で培養し、市販のLNPの細胞毒性試験を行った。
液体培地(RPMI−1640,FBS(+),PSN(+))中で培養されたMKN45細胞の入った10cm dishの培地をアスピレーションし、PBS溶液3mlで洗った。そこにトリプシン1mlを加え、5分間インキュベート(37℃,5%CO2)した。新しい培地を5ml加え、トリプシンの酵素反応を終了させた。合計6mlを1100rpmで5分間遠心した。この際、サンプル10μlを死細胞を染める色素トリパンブルーと混合し、血球計算版で生細胞数をカウントした。遠心後の上清をアスピレーションし、新しい培地2mlを加えた。そこから96wellプレートに、2×104cells/wellになるように100μlずつ合計48wellにLNP濃度10mg/mlから2倍希釈で10系統濃度を振り、コントロールとブランクを含めて12系統、n=4で細胞を播いた。一晩培養した後、各wellの培地を捨てPBS溶液100μlで洗い、100μlの新しい培地とPBSで10倍に希釈したMTTメタノール溶液を10μl、各wellに加えた。4時間インキュベートした後に10%SDSを100μl/well加え、一晩インキュベートし、570nm−660nmの吸光度を測定した。結果を図3に示す。
MKN45細胞をALA,LNP存在下でNIR照射し、細胞死が起こるか確認した。
液体培地(RPMI−1640,FBS(+),PSN(+))中で培養されたMKN45細胞の入った10cmdishの培地をアスピレーションし、PBS溶液3mlで洗った。そこにトリプシン1mlを加え、5分間インキュベート(37℃,5%CO2)した。新しい培地を5ml加え、トリプシンの酵素反応を終了させた。合計6mlを1100rpmで5分間遠心した。この際、サンプル10μlを死細胞を染める色素トリパンブルーと混合し、血球計算版で細胞数をカウントした。遠心後の上清をアスピレーションし、新しい培地2mlを加えた。そこから96wellプレートに、2×104cells/wellになるように100μlずつALA濃度1000,100,10,0μMとブランク用に播いた。それぞれLNP(+)とLNP(−)の系統を用意し、NIR(+)とNIR(−)用にプレートを2枚に分けた。一晩培養した後、培地を捨て新しい培地(LNP(+)はLNP 2.5mg/mlを含む)100μlと0.2MのALAを上述の濃度になるように調整し、添加した。4時間インキュベートした後に980nmのNIR(400mA)をプレートの50mm上方から3min/well照射した。一晩培養した後、各wellの培地を捨てPBS溶液100μlで洗い、100μlの新しい培地とPBSで10倍に希釈したMTTメタノール溶液を10μl、各wellに加えた。4時間インキュベートした後に10%SDSを100μl/well加え、一晩インキュベートし、570nm−660nmの吸光度を測定した。結果を図4に示す。
MKN45細胞を2×104cells/wellとし、ALA濃度を2000,1000,100,10,0μMとし、ALA添加後の培養時間を4時間から24時間に変更し、NIRの照射時間を90min/well照射する以外は、実施例4と同様に、市販LNPでのALA−PDTを行った。結果を図5に示す。
オレイン酸(OA)コートLNP(NaYF4;Yb/Er or Tm/Gd=18/2/30mol%)を合成した。
H2O 6mlにNaOH 1.2g,Ethanol 20ml,Oleic Acid 20ml,0.2M RECl3 8ml(H2O 8ml,YCl3・6H2O 244.7mg,YbCl3・6H2O 112.6mg,ErCl3・6H2O or TmCl3・6H2O 12.2mg,GdCl3・xH2O 114.5mg),2M NH4F 4ml(H2O 4ml,NH4F 298mg)を加え、オートクレーブで200℃,2時間1400回転で撹拌しながら反応させた。約2時間室温になるまで冷却し、10000rpmで10分間遠心した。上清を捨て、H2OとEtOHでそれぞれ3回ずつ洗浄した。
Cyclohexane 200mlに上述の方法で合成したOAコートLNP(NaYF4;Yb/Er or Tm/Gd=18/2/30mol%)200mg,tert−Butanol 140ml,H2O 20ml,5wr% K2CO3aq 10mlを加え室温で撹拌した。20分後、Lemieux von−Rudolff reagent 40ml(H2O 40ml,KMnO4 36.8mg,NaIO4 900.5mg)を加え、40℃で48時間オイルバス中で反応させた。反応後、10000rpmで10分間遠心し、H2O,acetone,EtOHで洗った。洗浄後、HCl(予めpH4〜5に調整)100mlを加え室温で30分撹拌した。その後反応液を10000rpmで10分間遠心し、H2Oで2回洗浄した。
上述の方法で合成したオレイン酸部位を酸化したLNP(NaYF4;Yb/Er/Gd=18/2/30 mol%)70mgをH2O 10mlに、NHS,EDCをそれぞれ700mgずつH2O 10mlに溶かし、室温で撹拌した。20分後、NEtMan 500mgをH2O 10mlに溶かしたものを加え4時間室温で反応させた。Amino Ethanol 10mlを加え、さらに4時間反応させた。反応後の溶液を10000rpmで10分間遠心し、LNPを回収した。回収したLNPをH2Oで洗浄した。
市販LNPに代えて実施例6で調製したオレイン酸コートLNPを用いる以外は実施例2と同様に、合成LNPによる一重項酸素の発生実験を行った。結果を図6に示す。
実施例6で調製した合成LNP及び市販LNPを用いる以外は実施例3と同様に、細胞毒性試験を行った。結果を図7に示す。
実施例6で調製した合成LNPの濃度を2mg/mLとし、ALA濃度を2000,1500,1000,100,0μMとする以外は、実施例5と同様に、合成LNPでのALA−PDTを行った。結果を図8に示す。
Claims (7)
- 赤外域光にてアップコンバージョン発光する粒子と、光増感剤又は5−アミノレブリン酸類とを含むことを特徴とする光線力学的治療又は診断剤。
- 赤外域光にてアップコンバージョン発光する粒子がランタニド粒子であることを特徴とする請求項1記載の光線力学的治療又は診断剤。
- ランタニド粒子がマンノースとの複合体であることを特徴とする請求項2記載の光線力学的治療又は診断剤。
- 光増感剤がテトラピロール化合物であることを特徴とする請求項1〜3のいずれか記載の光線力学的治療又は診断剤。
- 5−アミノレブリン酸類が、5−アミノレブリン酸若しくはその誘導体、又はこれらの塩であることを特徴とする請求項1〜3のいずれか記載の光線力学的治療又は診断剤。
- 赤外域光が、波長0.7μm〜2.5μmの近赤外光であることを特徴とする請求項1〜5のいずれか記載の光線力学的治療又は診断剤。
- がんの治療又は診断であることを特徴とする請求項1〜6のいずれか記載の光線力学的治療又は診断剤。
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