JP2010169677A - 有毛細胞標識剤、及び該標識剤を用いた有毛細胞標識方法 - Google Patents
有毛細胞標識剤、及び該標識剤を用いた有毛細胞標識方法 Download PDFInfo
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- JP2010169677A JP2010169677A JP2009292551A JP2009292551A JP2010169677A JP 2010169677 A JP2010169677 A JP 2010169677A JP 2009292551 A JP2009292551 A JP 2009292551A JP 2009292551 A JP2009292551 A JP 2009292551A JP 2010169677 A JP2010169677 A JP 2010169677A
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- hair cell
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- carboxylic acid
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- 238000002372 labelling Methods 0.000 title claims abstract description 108
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- 239000003795 chemical substances by application Substances 0.000 claims description 113
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 239000000126 substance Substances 0.000 claims description 56
- 238000010186 staining Methods 0.000 claims description 51
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 44
- 230000006870 function Effects 0.000 claims description 43
- 241000252212 Danio rerio Species 0.000 claims description 41
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 38
- 208000016354 hearing loss disease Diseases 0.000 claims description 35
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 35
- 241001465754 Metazoa Species 0.000 claims description 31
- 125000003277 amino group Chemical group 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 230000005284 excitation Effects 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 231100000419 toxicity Toxicity 0.000 claims description 25
- 230000001988 toxicity Effects 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 23
- 206010011878 Deafness Diseases 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 238000012216 screening Methods 0.000 claims description 18
- 238000012360 testing method Methods 0.000 claims description 16
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- 238000003384 imaging method Methods 0.000 claims description 12
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- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000000129 anionic group Chemical group 0.000 claims description 10
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- 238000011156 evaluation Methods 0.000 claims description 9
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- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims description 7
- 150000001734 carboxylic acid salts Chemical class 0.000 claims description 5
- 150000003460 sulfonic acids Chemical class 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 3
- -1 N-ethyl-N-phenylamino group Chemical group 0.000 description 106
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 13
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 12
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 12
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 12
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
- 125000001153 fluoro group Chemical group F* 0.000 description 12
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 210000000056 organ Anatomy 0.000 description 12
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
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Abstract
【解決手段】一般式(I)又は(II)で表される化合物から選択される少なくとも一種を有効成分として含む事を特徴とする有毛細胞標識剤、及び該標識剤を使用する有毛細胞標識方法。
【選択図】なし
Description
R1は、水素原子、アルキル基、又はアリール基を表し、
R2〜R5は、各々独立して水素原子、アルキル基、アリール基、アルコキシ基、カルボン酸基、スルホン酸基、ヘテロ環基、アミノ基、又はハロゲン原子を表し、R2とR3、R3とR4、又はR4とR5は互いに結合して環を形成しても良く、R6は、水素原子、又はアルキル基を表し、
R7は、水素原子、アルキル基、カルボン酸基、又はシアノ基を表し、
X1 -は、陰イオン性基を表し、
Yは、硫黄原子、酸素原子、−N(R8)−、又は−C(R9)(R10)−を表し、R8〜R10は、各々独立して、水素原子、アルキル基、又はアリール基を表し、R9とR10は互いに結合して環を形成しても良く、
Aは、アリール基、又はアルケニル基を表し、
nは、1〜3の整数を示し、nが1の時、AとR6は縮合して環を形成しても良い]
R11〜R12は、各々独立して、カルボン酸基、カルボン酸エステル、カルボン酸アミド基、スルホン酸基、スルホン酸エステル、スルホン酸アミド基、カルボン酸の塩、またはスルホン酸の塩を表し、
R13及びR14は、各々独立して、水素原子、アルキル基、又はアリール基を表し、R15、R16、R17A、及びR17Bは、各々独立して水素原子、アルキル基、アリール基、又はヘテロ環基を表し、
X2 -は、陰イオン性基を表す]
また、本発明に係る有毛細胞のイメージング方法は、
本発明の有毛細胞標識剤と生物試料とを接触させる工程と、
該生物試料に励起光を照射し、該有毛細胞標識剤に由来する蛍光を観察する工程と、
を含むことを特徴とする有毛細胞のイメージング方法である。
生物に化学物質を投与する工程と、
該生物と本発明の有毛細胞標識剤を接触させる工程と、
該生物に励起光を照射し、該有毛細胞標識剤に由来する蛍光を観察する工程と、
を含むことを特徴とする化学物質の聴覚毒性を評価する方法である。
難聴疾患モデル動物に被験物質を投与する工程と、
該モデル動物に本発明の聴覚機能診断用組成物を投与する工程と、
該モデル動物の有毛細胞に対する該聴覚機能診断用組成物の染色状態を調べる工程と、
を含む難聴疾患の治療薬又は予防薬のスクリーニング方法である。
難聴疾患モデル動物に被験物質を投与する工程と、
該モデル動物に本発明の聴覚機能診断用組成物を投与する工程と、
該モデル動物の有毛細胞に対する該聴覚機能診断用組成物の染色状態を調べる工程と、
を含む難聴疾患の治療薬又は予防薬の評価方法である。
得られた化合物(II)は、通常の有機化合物の単離・精製方法を用いる事ができる。例えば、反応液を塩酸等で酸性にして、酸析する事によって固体をろ別し、水酸化ナトリウム等で中和し、濃縮すれば、粗成物が得られる。更に、粗成物をアセトン、メタノール等を用いた再結晶、シリカゲルを用いたカラム精製等により精製する。これらの方法は、単独又は2つ以上組み合わせて精製を行う事により高純度で得る事が可能である。
本工程において、有毛細胞標識剤をゼブラフィッシュに投与する方法としては、特に限定されるものではないが、有毛細胞標識剤が水溶性の場合は、飼育水中に化学物質を共存させる方法、非水溶性の場合は、飼育水中に化学物質を単独で分散させて共存させる方法、または微量の界面活性剤やDMSOを共存させる方法、ゼブラフィッシュの餌に混ぜて経口投与する方法、又は、注射等によって非経口投与する方法が挙げられる。好ましくは、容易に出来る飼育水中に有毛細胞標識剤を共存させる方法が挙げられる。
[有毛細胞標識剤による染色]
化合物(1)をDMSOに溶解し、濃度1mg/mLになるように調製し、ストックソリューションとした。このストックソリューションを蒸留水で希釈し、色素濃度1μg/mLの有毛細胞染色液1を調製した。又、人工海水シーライフ(マリンテック社製)を60mg/Lで蒸留水に溶解して、Egg Waterを調整した。24穴マルチウエルプレートの任意の1箇所に5匹のゼブラフィッシュの稚魚(受精後7日胚)を飼育水ごと入れた。飼育水を廃棄し、有毛細胞染色液1を1mL加えた。1時間放置した後、ウエル中の有毛細胞染色液1を廃棄し、新鮮なEgg Water1mLで置換した。更に、Egg Waterを廃棄し、新鮮なEgg Water 1mLで置換する事を2回繰り返した。ウエルから稚魚をシャーレ上に1匹取り出し、メチルセルロースを加え稚魚の動きを制限し、実体蛍光顕微鏡で蛍光画像を撮影した。実体顕微鏡はライカマイクロシステムズ社製MZ16FAを使用した。
実施例1において使用した化合物(1)を表1に記載した化合物に変更した以外は、実施例1と同様の操作を行った。実体蛍光顕微鏡の撮像ユニット(オリンパス社製 顕微鏡用デジタルカメラ DP72)のIRカットフィルターを取り外すことにより、近赤外波長域の蛍光画像を取得できるように改造した。励起・蛍光波長が近赤外域にある化合物を用いる際には、この撮像ユニットを備えた実体蛍光顕微鏡を用い、実施例1と同様の操作を行った。
(比較例1)
実施例1において用いた化合物(1)を(2−(4−(dimethylamino)styryl)−N−ethylpyridinium iodide)(DASPEI)に変更し、色素濃度を250μg/mLとした以外は、実施例1と同様の操作を行った。
(比較例2)
実施例1において使用した化合物(1)を、FM1−43に変更した以外は、実施例1と同様の操作を行った。
(比較例3)
実施例1において使用した化合物(1)を、インドシアニングリーン(ICG)に変更し、色素濃度を250μg/mLとした以外は、実施例1と同様の操作を行った。
[蛍光強度の評価]
前記実施例1〜33、前記比較例1〜3を蛍光観察画像からそれぞれ、有毛細胞の蛍光強度を目視による評価(+++:強度に観測される、++:中度に観測される、+:弱度に観測される、染色しない)を行った。なお、化合物の励起波長および蛍光波長は、10mg/mLのDMSO溶液を精製水に500倍希釈した水溶液を日立ハイテク社製FL4500蛍光分光測定機で測定して求めた。
前記実施例1〜33、前記比較例1〜3を蛍光観察画像からそれぞれ、有毛細胞の染色性について目視による評価を行った。評価の基準は、B:大きいサイズの感丘が主に染色されるもの、S:小さいサイズの感丘が主に染色されるもの、BS:大きいサイズと小さいサイズの両方の感丘が染色されるもの、として評価した。
ゲンタマイシン等のアミノグリコシド系抗生物質や、シスプラチン等の抗がん剤にはヒトに対する聴覚毒性が指摘されている。このような聴覚毒性の疑いのある化学物質を、ヒトモデル生物に暴露し、本発明の有毛細胞標識剤による有毛細胞の染色性の変化を検出することで、化学物質の聴覚毒性を評価することが可能になる。
実施例34において使用したゲンタマイシン溶液を5μMのシスプラチン溶液に変更した以外は、実施例34と同様の操作を行った。
実施例34において使用したゲンタマイシン溶液を5μMのタウリン溶液に変更した以外は、実施例34と同様の操作を行った。
本発明の有毛細胞標識剤による細胞染色状態(染色強度や蛍光特性)の変化を指標として、細胞の状態(トランスクリプトーム、プロテオーム、メタボロームなど)や機能(viability、膜電位など)の変化を、検出・評価することができる。
atgMO 10μg/μL
フェノールレッド 0.005%
EGFP 50ng/μL
ゼブラフィッシュの受精後1時間以内(第二卵割期以前)の受精卵に、MO混合液をマイクロインジェクションした。マイクロインジェクションには、PC−10プーラー(ナリシゲ製)でガラス管を伸展切断し、断面をEG−400(ナリシゲ製)研磨器で研磨することにより先端を尖らせたガラス製毛細管(内径0.6mm)を使用した。10cmデッシュに1%アガロースを敷いたものの中に飼育水と受精卵を入れ、実体顕微鏡下でマイクロインジェクションした。インジェクションの際、ガラス製毛細管にはIM−9A(ナリシゲ製)の手動インジェクターあるいは、IM−30(ナリシゲ製)の電動マイクロインジェクターを接続し、圧力による注入を行った。MOの注入量は1受精卵あたり1−10ngとした。
本発明の有毛細胞標識剤には、その染色強度が、FM1−43のような従来知られた染色剤による染色強度に比べて、高いものが含まれる。このことを確認するために、染色剤の濃度を変化させて、染色性の変化を調べる実験を、次の様にして行った。
Claims (17)
- 一般式(I)又は(II)で表される化合物から選択される少なくとも一種を有効成分として含むことを特徴とする有毛細胞標識剤:
R1は、水素原子、アルキル基、又はアリール基を表し、
R2〜R5は、各々独立して水素原子、アルキル基、アリール基、アルコキシ基、カルボン酸基、スルホン酸基、ヘテロ環基、アミノ基、又はハロゲン原子を表し、R2とR3、R3とR4、又はR4とR5は互いに結合して環を形成しても良く、R6は、水素原子、又はアルキル基を表し、
R7は、水素原子、アルキル基、カルボン酸基、又はシアノ基を表し、
X1 -は、陰イオン性基を表し、
Yは、硫黄原子、酸素原子、−N(R8)−、又は−C(R9)(R10)−を表し、R8〜R10は、各々独立して、水素原子、アルキル基、又はアリール基を表し、R9とR10は互いに結合して環を形成しても良く、
Aは、アリール基、又はアルケニル基を表し、
nは、1〜3の整数を示し、nが1の時、AとR6は縮合して環を形成しても良い]、
R11〜R12は、各々独立して、カルボン酸基、カルボン酸エステル、カルボン酸アミド基、スルホン酸基、スルホン酸エステル、スルホン酸アミド基、カルボン酸の塩、またはスルホン酸の塩を表し、
R13及びR14は、各々独立して、水素原子、アルキル基、又はアリール基を表し、R15、R16、R17A、及びR17Bは、各々独立して水素原子、アルキル基、アリール基、又はヘテロ環基を表し、
X2 -は、陰イオン性基を表す]。 - 前記一般式(I)中のAのアルケニル基が下記一般式(III)で表される事を特徴とする請求項1に記載の有毛細胞標識剤:
R18〜R21は、各々独立して水素原子、アルキル基、アリール基、アルコキシ基、カルボン酸基、スルホン酸基、ヘテロ環基、アミノ基、又はハロゲン原子を表し、R18とR19、R19とR20、又はR20とR21は互いに結合して環を形成しても良く、R22は、水素原子、アルキル基、又はアリール基を表す。Zは硫黄原子、酸素原子、又は−C(R23)(R24)−を表し、R23〜R24は、水素原子、アルキル基、又はアリール基を表し、R23とR24は互いに結合して環を形成しても良い]。 - 前記一般式(I)中のAのアリール基が下記一般式(IV)で表される事を特徴とする請求項1に記載の有毛細胞標識剤:
R25は、水素原子、アルキル基、アラルキル基、アルケニル基、アリール基、ヘテロ環基、又はアシル基を表し、
R26〜R29は、各々独立して水素原子、アルキル基、アリール基、カルボン酸基、カルボン酸エステル基、又はアシル基を表し、R26とR28が互いに結合して環を形成しても良く、
R30は、水素原子、アルキル基、アルコキシ基、又はハロゲン原子を表す]。 - 前記一般式(IV)中で表されるR26とR28が互いに結合して形成される環が、脂肪族環である請求項3に記載の有毛細胞標識剤。
- 前記一般式(IV)中で表されるR26とR28が互いに結合して形成される環が、シクロペンタン環である請求項3に記載の有毛細胞標識剤。
- 前記一般式(II)中のR15、R16、R17A、及びR17Bの少なくとも1つ以上がアルキル基である事を特徴とする請求項1に記載の有毛細胞標識剤。
- 前記一般式(I)で表される化合物中にカルボン酸基、又はスルホン酸基を1つ以上有する事を特徴とする請求項1〜6の何れか1項に記載の有毛細胞標識剤。
- 請求項1に記載の化合物と生物試料とを接触させる工程を含むことを特徴とする有毛細胞の標識方法。
- 請求項1に記載の化合物と生物試料とを接触させる工程と、該生物試料に励起光を照射し、該化合物に由来する蛍光を観察する工程と、
を含むことを特徴とする有毛細胞のイメージング方法。 - 化学物質の聴覚毒性を評価する方法であって、
生物に化学物質を投与する工程と、
該生物と請求項1に記載の化合物を接触させる工程と、
該生物に励起光を照射し、該化合物に由来する蛍光を観察する工程と、
を含むことを特徴とする化学物質の聴覚毒性を評価する方法。 - 前記生物がゼブラフィッシュであることを特徴とする請求項10に記載の化学物質の聴覚毒性を評価する方法。
- 請求項1に記載の化合物を有効成分として含む聴覚機能診断用組成物。
- 前記有毛細胞標識剤が近赤外領域に蛍光を発する化合物であることを特徴とする請求項12に記載の聴覚機能診断用組成物。
- 難聴疾患の治療薬又は予防薬をスクリーニングする方法であって、
難聴疾患モデル動物に被験物質を投与する工程と、
該モデル動物に請求項12に記載の聴覚機能診断用組成物を投与する工程と、
該モデル動物の有毛細胞に対する該聴覚機能診断用組成物の染色状態を調べる工程と、
を含む難聴疾患の治療薬又は予防薬のスクリーニング方法。 - 前記難聴疾患モデル動物がゼブラフィッシュである請求項14に記載のスクリーニング方法。
- 難聴疾患の治療薬又は予防薬を評価する方法であって、
難聴疾患モデル動物に被験物質を投与する工程と、
該モデル動物に請求項12に記載の聴覚機能診断用組成物を投与する工程と、
該モデル動物の有毛細胞に対する該聴覚機能診断用組成物の染色状態を調べる工程と、
を含む難聴疾患の治療薬又は予防薬の評価方法。 - 前記難聴疾患モデル動物がゼブラフィッシュである請求項16に記載の評価方法。
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WO2011077733A1 (ja) | 2009-12-25 | 2011-06-30 | キヤノン株式会社 | 経鼻中枢神経系組織標識用組成物、経鼻中枢神経系組織標識用組成物を用いた標識方法及びスクリーニング方法 |
WO2014042262A1 (ja) * | 2012-09-13 | 2014-03-20 | 国立大学法人 東北大学 | 難聴が生じにくいモデル動物 |
JP2015522798A (ja) * | 2012-05-18 | 2015-08-06 | アンスティテュ ギュスターブ ルシ (アイジーアール) | 赤色および遠赤外蛍光色素を用いた生物組織の細胞レベルにおける特性評価 |
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JP2015522798A (ja) * | 2012-05-18 | 2015-08-06 | アンスティテュ ギュスターブ ルシ (アイジーアール) | 赤色および遠赤外蛍光色素を用いた生物組織の細胞レベルにおける特性評価 |
WO2014042262A1 (ja) * | 2012-09-13 | 2014-03-20 | 国立大学法人 東北大学 | 難聴が生じにくいモデル動物 |
JP2016519080A (ja) * | 2013-03-15 | 2016-06-30 | ビセン メディカル, インコーポレイテッド | 4,4−二置換シクロヘキシル架橋ヘプタメチンシアニン色素およびその使用 |
JP2019151665A (ja) * | 2013-03-15 | 2019-09-12 | ビセン メディカル, インコーポレイテッド | 4,4−二置換シクロヘキシル架橋ヘプタメチンシアニン色素およびその使用 |
JP7018913B2 (ja) | 2013-03-15 | 2022-02-14 | ビセン メディカル, インコーポレイテッド | 4,4-二置換シクロヘキシル架橋ヘプタメチンシアニン色素およびその使用 |
JP2017503004A (ja) * | 2013-10-31 | 2017-01-26 | ベス・イスラエル・ディーコネス・メディカル・センター,インコーポレイテッド | 近赤外蛍光造影バイオイメージング剤及びその使用方法 |
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JP7423547B2 (ja) | 2018-01-26 | 2024-01-29 | ユニヴェルシテ・ドゥ・ストラスブール | 医療機器用蛍光ポリマーコーティングフィルム |
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EP2204194A2 (en) | 2010-07-07 |
US8460639B2 (en) | 2013-06-11 |
EP2204194A3 (en) | 2010-09-08 |
US20100166663A1 (en) | 2010-07-01 |
JP5783673B2 (ja) | 2015-09-24 |
EP2428230A1 (en) | 2012-03-14 |
EP2204194B1 (en) | 2017-08-02 |
US20130219529A1 (en) | 2013-08-22 |
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