JP5783673B2 - 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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- JP5783673B2 JP5783673B2 JP2009292551A JP2009292551A JP5783673B2 JP 5783673 B2 JP5783673 B2 JP 5783673B2 JP 2009292551 A JP2009292551 A JP 2009292551A JP 2009292551 A JP2009292551 A JP 2009292551A JP 5783673 B2 JP5783673 B2 JP 5783673B2
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- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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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−B)で表される化合物又はその塩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、置換若しくは無置換のアルキル基、又は置換若しくは無置換のアリール基を表し、
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、
X-は、陰イオン性基を表し、
Yは、硫黄原子、酸素原子、又は−N(R8)−を表し、R8は、水素原子、アルキル基、又はアリール基を表し、
nは1〜3の整数を示し、
Aは、下記一般式(III)で表される事を特徴とする有毛細胞標識剤:
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、置換若しくは無置換のアルキル基、又は置換若しくは無置換のアリール基を表し、
Zは硫黄原子、酸素原子を表す]。 - 一般式(I−C)で表される化合物又はその塩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、置換若しくは無置換のアルキル基、又は置換若しくは無置換のアリール基を表し、
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、
X-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、
nは1〜3の整数を示し、
Aは、下記一般式(IV)で表される事を特徴とする有毛細胞標識剤:
R25は、水素原子、置換若しくは無置換のアルキル基、置換若しくは無置換のアラルキル基、置換若しくは無置換のアルケニル基、置換若しくは無置換のアリール基、置換若しくは無置換のヘテロ環基、又は置換若しくは無置換のアシル基を表し、
R26〜R29は、各々独立して水素原子、置換若しくは無置換のアルキル基、置換若しくは無置換のアリール基、カルボン酸基、置換若しくは無置換のカルボン酸エステル基、又は置換若しくは無置換のアシル基を表し、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が互いに結合して環を形成し、該環が、脂肪族環である請求項2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が互いに結合して環を形成し、該環が、シクロペンタン環である請求項2に記載の有毛細胞標識剤。
- 下記式(13)及び(20):
- R1が、アルキル基、又は置換基としてカルボン酸基、スルホン酸基若しくはポリエチレングリコール基を有するアルキル基である請求項1乃至4のいずれか一項に記載の有毛細胞標識剤。
- 下記式(1)、(4)、(6)、(8)、(9)、(15)、(16)、(25)、(28)、(30)、(32)、(39)、(40)、(45)、(47)、(50)、(51)及び(53)で表される化合物のうち少なくとも1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;
- 請求項1乃至7のいずれか一項に記載の有毛細胞標識剤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乃至7のいずれか一項に記載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(ヒトを除く)に化学物質を投与する工程と、
該生物と請求項1乃至7のいずれか一項に記載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。 - 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乃至7のいずれか一項に記載の化合物又はその塩の少なくとも1種を有効成分として含む聴覚機能診断用組成物。
- 前記化合物又はその塩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または13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または13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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EP2370111B1 (en) | 2008-12-25 | 2014-11-05 | Canon Kabushiki Kaisha | Probe for a biological specimen and labelling method and screening method using the probe |
JP5733715B2 (ja) * | 2009-12-25 | 2015-06-10 | 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 |
US20150104394A1 (en) * | 2012-05-18 | 2015-04-16 | Igr-Institut Gustave Roussy | Characterization of biological tissues at a cellular level using red and far-red fluorescent dyes |
US20160015011A1 (en) * | 2012-09-13 | 2016-01-21 | Tohoku University | Animal model resistant to hearing loss |
AU2014228808C1 (en) * | 2013-03-15 | 2018-12-20 | Visen Medical, Inc. | 4,4-disubstituted cyclohexyl bridged heptamethine cyanine dyes and uses thereof |
US11077210B2 (en) * | 2013-10-31 | 2021-08-03 | Beth Israel Deaconess Medical Center | Near-infrared fluorescent contrast bioimaging agents and methods of use thereof |
US11001562B2 (en) | 2013-10-31 | 2021-05-11 | Beth Israel Deaconess Medical Center | Near-infrared fluorescent nerve contrast agents and methods of use thereof |
KR20150089702A (ko) * | 2014-01-28 | 2015-08-05 | 제일모직주식회사 | 신규 화합물, 신규 폴리머, 이를 포함하는 착색제, 이를 포함하는 감광성 수지 조성물 및 컬러필터 |
EP3517146A1 (en) * | 2018-01-26 | 2019-07-31 | Université de Strasbourg | Fluorescent polymeric coating film for medical devices |
CN111100627A (zh) * | 2019-12-20 | 2020-05-05 | 中国科学院化学研究所 | 荧光探针及其应用 |
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US3933596A (en) * | 1974-04-01 | 1976-01-20 | The Lummus Company | Desulfurization of coke |
DE3832903A1 (de) * | 1987-09-29 | 1989-04-06 | Fuji Photo Film Co Ltd | Elektrophotographische druckplatte |
JP2649692B2 (ja) * | 1988-05-18 | 1997-09-03 | コニカ株式会社 | ハロゲン化銀写真感光材料 |
US5350580A (en) * | 1990-03-05 | 1994-09-27 | Minnesota Mining And Manufacturing Company | Device and method for extended delivery of pharmacologically active agents to the ear |
JP3285609B2 (ja) * | 1991-06-21 | 2002-05-27 | キヤノン株式会社 | 標識複合体、及びそれを用いる分析法 |
US5421818A (en) | 1993-10-18 | 1995-06-06 | Inner Ear Medical Delivery Systems, Inc. | Multi-functional inner ear treatment and diagnostic system |
DE69532472T2 (de) * | 1994-06-30 | 2004-10-28 | Minnesota Mining And Mfg. Co., Saint Paul | Die härtung anzeigende form- und beschichtungsmasse |
DE19732016A1 (de) | 1997-07-25 | 1999-01-28 | Henkel Kgaa | Haarfärbemittel |
DE19926377A1 (de) | 1999-06-10 | 2000-12-14 | Henkel Kgaa | Mittel zum Färben von keratinhaltigen Fasern |
JP4150489B2 (ja) * | 2000-06-27 | 2008-09-17 | 花王株式会社 | 染毛剤組成物 |
US6579718B1 (en) * | 2000-08-04 | 2003-06-17 | Molecular Probes, Inc. | Carbazolylvinyl dye protein stains |
JP2005082678A (ja) * | 2003-09-08 | 2005-03-31 | Mitsubishi Paper Mills Ltd | 光電変換材料、半導体電極並びにそれを用いた光電変換素子 |
DK1732567T3 (da) * | 2004-03-29 | 2009-02-09 | Sod Conseils Rech Applic | Anvendelse af et phenothiazin-derivat til at forhindre og/eller behandle höretab |
US20060188445A1 (en) * | 2005-02-22 | 2006-08-24 | Fred Hutchinson Cancer Research Center | Assay for compounds that protect against sensory hair cell death and compounds identified by same |
JP2007048672A (ja) * | 2005-08-11 | 2007-02-22 | Mitsubishi Paper Mills Ltd | 光電変換材料、半導体電極並びにそれを用いた光電変換素子 |
JP2007048680A (ja) * | 2005-08-12 | 2007-02-22 | Mitsubishi Paper Mills Ltd | 光電変換材料、半導体電極並びにそれを用いた光電変換素子 |
US7951845B2 (en) * | 2006-01-19 | 2011-05-31 | The Regents Of The University Of Michigan | Composition and method of treating hearing loss |
EP1813263A1 (en) | 2006-01-27 | 2007-08-01 | Wella Aktiengesellschaft | Agent for the nonoxidative coloring of hair |
JP2008094897A (ja) * | 2006-10-10 | 2008-04-24 | Canon Inc | 色素化合物及び該色素化合物を含むインク |
WO2008127139A1 (fr) | 2007-04-11 | 2008-10-23 | Institut Molekulyarnoi Biologii Im. V.A. Engeldardta Rossiiskoi Akademii Nauk | Colorants d'indocyanine fluorescents et leurs dérivés destinés à l'analyse de macromolécules biologiques |
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