JP7371476B2 - Near-infrared fluorescent composition and near-infrared fluorescent labeling agent - Google Patents
Near-infrared fluorescent composition and near-infrared fluorescent labeling agent Download PDFInfo
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- JP7371476B2 JP7371476B2 JP2019224411A JP2019224411A JP7371476B2 JP 7371476 B2 JP7371476 B2 JP 7371476B2 JP 2019224411 A JP2019224411 A JP 2019224411A JP 2019224411 A JP2019224411 A JP 2019224411A JP 7371476 B2 JP7371476 B2 JP 7371476B2
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- infrared fluorescent
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- fluorescent dye
- water
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- KRTNITDCKAVIFI-UHFFFAOYSA-N tridecyl benzenesulfonate Chemical compound CCCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 KRTNITDCKAVIFI-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- XQXWVKQIQQTRDJ-UHFFFAOYSA-N undecyl benzenesulfonate Chemical compound CCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 XQXWVKQIQQTRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Landscapes
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Description
本発明は、近赤外蛍光組成物およびそれを用いた蛍光標識剤に関する。 The present invention relates to a near-infrared fluorescent composition and a fluorescent labeling agent using the same.
タンパク質や細胞、組織などを可視化するバイオイメージング法は、生体内分子・細胞機能の解明や創薬の研究等、生物学、医学の研究領域で幅広く活用されている。中でも蛍光色素を用いたバイオイメージング法は、現象の動的な観察、多色観察、高感度観察が可能なイメージング法である。さらに、近年では、蛍光色素を用いたバイオイメージング法は非侵襲的に診断可能なイメージング法として注目されており、患者への負担が少ない画像診断や手術中のリアルタイム診断など臨床現場における応用が期待されている。 Bioimaging methods for visualizing proteins, cells, tissues, etc. are widely used in biological and medical research fields, such as elucidation of in-vivo molecules and cell functions and drug discovery research. Among these, bioimaging methods using fluorescent dyes are imaging methods that enable dynamic observation of phenomena, multicolor observation, and high-sensitivity observation. Furthermore, in recent years, bioimaging methods using fluorescent dyes have attracted attention as imaging methods that enable non-invasive diagnosis, and are expected to be applied in clinical settings, such as image diagnosis with less burden on patients and real-time diagnosis during surgery. has been done.
バイオイメージングに用いられる蛍光色素としては、可視光領域に蛍光を発するものが広く使用されているが、この波長領域は細胞や組織の自家蛍光や、吸収・散乱が高いため、深部の観察が困難であった。そこで、より影響を受けにくい７００ｎｍ以上の近赤外領域に蛍光を発する蛍光色素を用いた検討が行われている（例えば、非特許文献１）。 As fluorescent dyes used in bioimaging, those that emit fluorescence in the visible light range are widely used, but this wavelength range is difficult to observe deep tissue due to the autofluorescence of cells and tissues, as well as high absorption and scattering. Met. Therefore, studies are being conducted using fluorescent dyes that emit fluorescence in the near-infrared region of 700 nm or more, which is less susceptible to the effects (for example, Non-Patent Document 1).
現在、バイオイメージングに用いられる近赤外蛍光色素としては、インドシアニングリーンなどのシアニン系色素が一般的に知られている。しかしながら、シアニン系色素は水溶液中での蛍光量子収率は数％と極めて低く、また、励起光による退色の懸念がある。 Currently, cyanine dyes such as indocyanine green are generally known as near-infrared fluorescent dyes used for bioimaging. However, cyanine dyes have extremely low fluorescence quantum yields of several percent in aqueous solutions, and there is also concern about fading due to excitation light.
一般的に、バイオイメージングに用いられる蛍光色素は、生体親和性を考慮して水溶性であるが、近赤外域での蛍光を有する分子構造とするためには、共役系の増大などが必要であるため、分子量は増加傾向となり、そのため、色素間に働く疎水性相互作用が強まり、会合や凝集が生じ易くなる。そして、蛍光量子収率の低下を招く。さらに、近赤外領域では、そのエネルギーレベルが水分子の振動エネルギーに近いことから、周囲に存在する水分子へのエネルギー移動が生じて、蛍光量子収率は低下する。 Fluorescent dyes used for bioimaging are generally water-soluble in consideration of biocompatibility, but in order to create a molecular structure with fluorescence in the near-infrared region, it is necessary to increase the number of conjugated systems. As a result, the molecular weight tends to increase, which strengthens the hydrophobic interactions between the dyes, making them more likely to cause association and aggregation. This results in a decrease in fluorescence quantum yield. Furthermore, in the near-infrared region, since the energy level is close to the vibrational energy of water molecules, energy transfer to surrounding water molecules occurs, and the fluorescence quantum yield decreases.
本発明が解決しようとする課題は、色素に対する両親媒性物質の割合を減少させても蛍光強度の低下が抑制された、７００ｎｍ以上の光波長で蛍光標識剤として好適に使用できる近赤外蛍光組成物を提供することである。 The problem to be solved by the present invention is to provide near-infrared fluorescence that can be suitably used as a fluorescent labeling agent at a light wavelength of 700 nm or more, and which suppresses a decrease in fluorescence intensity even when the ratio of amphiphilic substance to dye is reduced. An object of the present invention is to provide a composition.
本発明者らは、鋭意検討を重ねた結果、Ｔｗｅｅｎ（登録商標）８０の量を変化させた場合のモル吸光係数と絶対蛍光量子収率との積の割合が、特定の基準を満たす非水溶性の近赤外蛍光色素を含む近赤外蛍光組成物が、上記課題を解決し得ることを見出し、本発明に至った。 As a result of extensive studies, the present inventors found that the ratio of the product of the molar extinction coefficient and the absolute fluorescence quantum yield when changing the amount of Tween (registered trademark) 80 was determined to be The inventors have discovered that a near-infrared fluorescent composition containing a fluorescent near-infrared fluorescent dye can solve the above-mentioned problems, leading to the present invention.
すなわち、本発明は、近赤外蛍光色素と、両親媒性物質と、水とを含んでなる近赤外蛍光組成物であって、近赤外蛍光色素が、非水溶性であり、かつ７００ｎｍ以上に極大蛍光波長を有し、下記式（１）を満たすことを特徴とする近赤外蛍光組成物に関する。
式（１） （εａ×Φａ）／（εｂ×Φｂ）≧０．３
ただし、
εａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近蛍光色素の絶対蛍光量子収率、
εｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素の絶対蛍光量子収率、
を表す。
That is, the present invention provides a near-infrared fluorescent composition comprising a near-infrared fluorescent dye, an amphiphilic substance, and water, wherein the near-infrared fluorescent dye is water-insoluble and The present invention relates to a near-infrared fluorescent composition having a maximum fluorescence wavelength as described above and satisfying the following formula (1).
Formula (1) (εa×Φa)/(εb×Φb)≧0.3
however,
εa is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
Φa is the absolute fluorescence quantum yield of the near-fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
εb is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
Φb is the absolute fluorescence quantum yield of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
represents.
さらに、本発明は、近赤外蛍光色素が、原子数３以上の置換基を有し、かつ３価または４価の中心金属を有するフタロシアニン系色素である上記近赤外蛍光組成物に関する。 Furthermore, the present invention relates to the above-described near-infrared fluorescent composition, wherein the near-infrared fluorescent dye is a phthalocyanine dye having a substituent having three or more atoms and a trivalent or tetravalent central metal.
さらに、本発明は、上記近赤外蛍光組成物を含む近赤外蛍光標識剤に関する。 Furthermore, the present invention relates to a near-infrared fluorescent labeling agent containing the above-mentioned near-infrared fluorescent composition.
本発明により、高い蛍光強度を有する近赤外蛍光組成物を用いた蛍光標識剤を提供することができるようになった。 According to the present invention, it has become possible to provide a fluorescent labeling agent using a near-infrared fluorescent composition having high fluorescence intensity.
以下、本発明の実施形態について説明するが、本発明はこれらに限定されるものではない。 Embodiments of the present invention will be described below, but the present invention is not limited thereto.
本実施形態に関わる近赤外蛍光組成物は、近赤外蛍光色素と、両親媒性物質と、水とを含む。そして、近赤外蛍光色素は、非水溶性であり、かつ７００ｎｍ以上に極大蛍光波長を有し、下記式（１）を満たすことを特徴としている。
式（１） （εａ×Φａ）／（εｂ×Φｂ）≧０．３
ただし、
εａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素の絶対蛍光量子収率、
εｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素の絶対蛍光量子収率、
を表す。
The near-infrared fluorescent composition according to this embodiment includes a near-infrared fluorescent dye, an amphipathic substance, and water. The near-infrared fluorescent dye is characterized in that it is water-insoluble, has a maximum fluorescence wavelength of 700 nm or more, and satisfies the following formula (1).
Formula (1) (εa×Φa)/(εb×Φb)≧0.3
however,
εa is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
Φa is the absolute fluorescence quantum yield of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
εb is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
Φb is the absolute fluorescence quantum yield of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
represents.
ここで、近赤外蛍光色素は、Ｔｗｅｅｎ ８０を含む水溶液中で可溶化されており、Ｔｗｅｅｎ ８０の量に依って単量体あるいは会合体、凝集体の状態で存在する。近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液では、近赤外蛍光色素が単量体として存在するために充分な量のＴｗｅｅｎ ８０が存在すると考えられ、近赤外蛍光色素のモル吸光係数や絶対蛍光量子収率は有機溶媒に溶解している状態での値に近いものとなる。一方、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ８０を含む水溶液では、近赤外蛍光色素は会合体や凝集体で存在する傾向が強くなるため、モル吸光係数や絶対蛍光量子収率は低下する。 Here, the near-infrared fluorescent dye is solubilized in an aqueous solution containing Tween 80, and exists in the form of a monomer, an aggregate, or an aggregate depending on the amount of Tween 80. In an aqueous solution containing Tween 80 that is 500 times the mass of the near-infrared fluorescent dye, it is thought that a sufficient amount of Tween 80 exists for the near-infrared fluorescent dye to exist as a monomer, and the near-infrared fluorescent dye The molar absorption coefficient and absolute fluorescence quantum yield of are close to the values when dissolved in an organic solvent. On the other hand, in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye, the near-infrared fluorescent dye has a strong tendency to exist in aggregates or aggregates, so the molar extinction coefficient and absolute fluorescence quantum yield are descend.
一般に、蛍光分子の蛍光強度はモル吸光係数と蛍光量子収率に比例する。したがって上記式（１）は、近赤外蛍光色素が単量体として存在する場合と、会合や凝集が進んだ場合との、蛍光強度の割合を規定するものである。上記式（１）を満たすとき、Ｔｗｅｅｎ８０の量が少ない場合でも、近赤外蛍光色素の蛍光強度の低下割合を小さく抑えることができる。 Generally, the fluorescence intensity of a fluorescent molecule is proportional to the molar extinction coefficient and fluorescence quantum yield. Therefore, the above formula (1) defines the ratio of fluorescence intensity between when the near-infrared fluorescent dye exists as a monomer and when association or aggregation has progressed. When the above formula (1) is satisfied, even when the amount of Tween 80 is small, the rate of decrease in the fluorescence intensity of the near-infrared fluorescent dye can be suppressed to a small level.
Ｔｗｅｅｎ ８０とは、モノオレイン酸ポリオキシエチレンソルビタンを指し、医薬品や食品、化粧品などで広く用いられている非イオン界面活性剤の一種である。 Tween 80 refers to polyoxyethylene sorbitan monooleate, which is a type of nonionic surfactant widely used in pharmaceuticals, foods, cosmetics, and the like.
（近赤外蛍光色素）
本発明における近赤外蛍光色素は、非水溶性であること、７００ｎｍ以上に極大蛍光波長を有することおよび上記式（１）を満たすものであれば、特に限定されるものではない。
(Near-infrared fluorescent dye)
The near-infrared fluorescent dye in the present invention is not particularly limited as long as it is water-insoluble, has a maximum fluorescence wavelength of 700 nm or more, and satisfies the above formula (1).
近赤外蛍光色素としては、シアニン系色素、フタロシアニン系色素、スクアリリウム系色素、ローダミン系色素およびボロンジピロメテン系色素などを好適に用いることができる。これらの色素は一種類のみを使用してもよく、二種類以上を混合して使用してもよい。 As the near-infrared fluorescent dye, cyanine dyes, phthalocyanine dyes, squarylium dyes, rhodamine dyes, boron dipyrromethene dyes, and the like can be suitably used. These dyes may be used alone or in combination of two or more.
近赤外蛍光色素は、非水溶性であることから、例えば、スルホン基、カルボキシル基、水酸基およびアミノ基などの親水基を持たない分子構造が好ましく、イオン結合も有さないことがより好ましい。水分子の振動エネルギーは近赤外領域のエネルギーレベルに近いため、近赤外蛍光色素の周囲に水分子が存在する場合、励起エネルギーは水分子の振動へのエネルギー移動により緩和され、蛍光量子収率は低下してしまう。 Since the near-infrared fluorescent dye is water-insoluble, it preferably has a molecular structure that does not have a hydrophilic group such as a sulfone group, a carboxyl group, a hydroxyl group, or an amino group, and more preferably does not have an ionic bond. The vibrational energy of water molecules is close to the energy level in the near-infrared region, so when water molecules exist around a near-infrared fluorescent dye, the excitation energy is relaxed by the energy transfer to the vibrations of the water molecules, resulting in fluorescence quantum loss. rate will drop.
さらに、会合や凝集が起りにくい分子構造であることが好ましい。例えば、近赤外蛍光色素は、原子数３以上の置換基を有し、かつ３価または４価の中心金属を有するフタロシアニン系色素であることが好ましく、下記一般式（１）または一般式（２）で表されるフタロシアニン系色素であることがより好ましい。また、置換基の原子数における下限値は、好ましくは３以上であるが、より好ましくは５以上、さらに好ましくは１０以上である。また、置換基の原子数における上限値は、特に制限はないが、概ね１００以下であることが好ましい。
このような構造を有するフタロシアニン系色素は、立体障害を引き起こす置換基を分子面に平行な方向（Ｒ1～Ｒ16およびＲ22～Ｒ45）、および分子面に垂直な方向（Ｚ）に有することができるため、より好適に用いることができる。
Furthermore, it is preferable that the molecular structure is such that association and aggregation are unlikely to occur. For example, the near-infrared fluorescent dye is preferably a phthalocyanine dye having a substituent having 3 or more atoms and a trivalent or tetravalent central metal, and is preferably a phthalocyanine dye having the following general formula (1) or the general formula ( A phthalocyanine dye represented by 2) is more preferable. Further, the lower limit of the number of atoms of the substituent is preferably 3 or more, more preferably 5 or more, still more preferably 10 or more. Further, the upper limit of the number of atoms of the substituent is not particularly limited, but it is preferably approximately 100 or less.
Phthalocyanine dyes having such a structure have substituents that cause steric hindrance in the direction parallel to the molecular plane (R 1 to R 16 and R 22 to R 45 ) and in the direction perpendicular to the molecular plane (Z). Therefore, it can be used more suitably.
一般式（１）
一般式（２）
一般式（１）および一般式（２）において、Ｒ1～Ｒ16およびＲ22～Ｒ45は、それぞれ独立に、水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアリール基、置換基を有してもよいシクロアルキル基、置換基を有してもよい複素環基、置換基を有してもよいアルコキシ基、置換基を有してもよいアリールオキシ基、置換基を有してもよいアルキルチオ基、置換基を有してもよいアリールチオ基を表す。ただし、Ｒ1～Ｒ16の内少なくとも一つおよびＲ22～Ｒ45の内少なくとも一つは、原子数３以上の基である。Ｍは、３価または４価の金属原子を表す。Ｚは、置換基を有してもよいアルコキシ基、置換基を有してもよいアリールオキシ基、－ＯＰ（＝Ｏ）Ｒ17Ｒ18、あるいは－ＯＳｉＲ19Ｒ20Ｒ21を表す。ここでＲ17、Ｒ18、Ｒ19、Ｒ20、Ｒ21は、それぞれ独立に、水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアリール基、置換基を有してもよいアルコキシ基、あるいは置換基を有してもよいアリールオキシ基を表す。ｎは１または２の整数を表し、Ｍが３価の金属原子である場合１であり、Ｍが４価の金属原子である場合２である。 In general formulas (1) and (2), R 1 to R 16 and R 22 to R 45 each independently represent a hydrogen atom, an alkyl group that may have a substituent, and a substituent-containing alkyl group. aryl group that may have a substituent, cycloalkyl group that may have a substituent, heterocyclic group that may have a substituent, alkoxy group that may have a substituent, aryloxy that may have a substituent represents an alkylthio group that may have a substituent or an arylthio group that may have a substituent. However, at least one of R 1 to R 16 and at least one of R 22 to R 45 are groups having 3 or more atoms. M represents a trivalent or tetravalent metal atom. Z represents an alkoxy group which may have a substituent, an aryloxy group which may have a substituent, -OP(=O)R 17 R 18 , or -OSiR 19 R 20 R 21 . Here, R 17 , R 18 , R 19 , R 20 and R 21 each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, and a substituent. It represents an alkoxy group which may have a substituent or an aryloxy group which may have a substituent. n represents an integer of 1 or 2; when M is a trivalent metal atom, it is 1; when M is a tetravalent metal atom, it is 2.
一般式（１）および一般式（２）において、アルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ヘキシル基、ヘプチル基、オクチル基、デシル基、ドデシル基、ペンタデシル基、オクタデシル基等が挙げられる。アルキル基の炭素数は、１～１８であることが好ましい。 In general formula (1) and general formula (2), examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and isopentyl group. group, hexyl group, heptyl group, octyl group, decyl group, dodecyl group, pentadecyl group, octadecyl group and the like. The alkyl group preferably has 1 to 18 carbon atoms.
アリール基としては、単環、縮合環、環集合およびこれらの組合せからなる構造が挙げられる。単環構造としては、フェニル基、ｏ－トリル基、ｍ－トリル基、ｐ－トリル基、２，４－キシリル基、ｐ－クメニル基、メシチル基等が挙げられ、炭素数は、６～１８であることが好ましい。縮合環構造としては、１－ナフチル基、２－ナフチル基、１－アントリル基、２－アントリル基、９－アントリル基、１－フェナンスリル基、９－フェナンスリル基、１－アセナフチル基等が挙げられ、炭素数は、１０～１８であることが好ましい。環集合構造としては、ｏ－ビフェニリル基、ｍ－ビフェニリル基、ｐ－ビフェニリル基等が挙げられ、炭素数は、１２～１８であることが好ましい。 Examples of the aryl group include structures consisting of a single ring, a condensed ring, a ring assembly, and a combination thereof. Examples of the monocyclic structure include phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,4-xylyl group, p-cumenyl group, mesityl group, and the number of carbon atoms is 6 to 18. It is preferable that Examples of the fused ring structure include 1-naphthyl group, 2-naphthyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 9-phenanthryl group, 1-acenaphthyl group, etc. The number of carbon atoms is preferably 10 to 18. Examples of the ring structure include o-biphenylyl group, m-biphenylyl group, p-biphenylyl group, and the number of carbon atoms is preferably 12 to 18.
シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、シクロオクタデシル基等が挙げられる。シクロアルキル基の炭素数は、３～１８であることが好ましい。 Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclooctadecyl group. The number of carbon atoms in the cycloalkyl group is preferably 3 to 18.
複素環基としては、脂肪族複素環、芳香族複素環が挙げられる。脂肪族複素環としては、イミダゾリジン環、２－イミダゾリン環、ピロリジン環、２－ピロリン環、ピペリジン環、ピペラジン環等の脂肪族複素環が挙げられる。また、芳香族複素環としては、イミダゾール環、チアゾール環、ピリジン環、ピラジン環等の芳香族複素環が挙げられる。 Examples of the heterocyclic group include aliphatic heterocycles and aromatic heterocycles. Examples of the aliphatic heterocycle include aliphatic heterocycles such as an imidazolidine ring, a 2-imidazoline ring, a pyrrolidine ring, a 2-pyrroline ring, a piperidine ring, and a piperazine ring. Further, examples of the aromatic heterocycle include aromatic heterocycles such as an imidazole ring, a thiazole ring, a pyridine ring, and a pyrazine ring.
アルコキシ基としては、直鎖又は分岐アルコキシ基が挙げられ、具体的には、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｔｅｒｔ－ブトキシ基、ネオペンチルオキシ基、２，３－ジメチル－３－ペンチルオキシ基、ｎ－へキシルオキシ基、ｎ－オクチルオキシ基、ステアリルオキシ基、２－エチルへキシルオキシ基等が挙げられる。アルコキシ基の炭素数は、１～６が好ましい。 Examples of the alkoxy group include straight chain or branched alkoxy groups, specifically methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, and neopentyloxy group. , 2,3-dimethyl-3-pentyloxy group, n-hexyloxy group, n-octyloxy group, stearyloxy group, 2-ethylhexyloxy group and the like. The number of carbon atoms in the alkoxy group is preferably 1 to 6.
アリールオキシ基としては、単環または縮合環を有するアリールオキシ基等が挙げられ、単環のアリールオキシ基であることが好ましい。単環のアリールオキシ基としては、フェノキシ基、ｐ－メチルフェノキシ基等が挙げられる。また、縮合環のアリールオキシ基としては、ナフチルオキシ基、アンスリルオキシ基等が挙げられる。アリールオキシ基の炭素数は、６～１２であることが好ましい。 Examples of the aryloxy group include aryloxy groups having a single ring or condensed rings, and a monocyclic aryloxy group is preferred. Examples of the monocyclic aryloxy group include a phenoxy group and a p-methylphenoxy group. Further, examples of the aryloxy group of the condensed ring include a naphthyloxy group, an anthryloxy group, and the like. The number of carbon atoms in the aryloxy group is preferably 6 to 12.
アルキルチオ基としては、メチルチオ基、エチルチオ基、プロピルチオ基、ブチルチオ基、ペンチルチオ基、ヘキシルチオ基、オクチルチオ基、デシルチオ基、ドデシルチオ基、オクタデシルチオ基、メトキシエチルチオ基、アミノエチルチオ基、ベンジルアミノエチルチオ基、メチルカルボニルアミノエチルチオ基、フェニルカルボニルアミノエチルチオ基などが挙げられる。 Examples of alkylthio groups include methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group, hexylthio group, octylthio group, decylthio group, dodecylthio group, octadecylthio group, methoxyethylthio group, aminoethylthio group, benzylaminoethylthio group. group, methylcarbonylaminoethylthio group, phenylcarbonylaminoethylthio group, and the like.
アリールチオ基としては、フェニルチオ基、１－ナフチルチオ基、２－ナフチルチオ基、９－アンスリルチオ基、クロロフェニルチオ基、トリフルオロメチルフェニルチオ基、シアノフェニルチオ基、ニトロフェニルチオ基、２－アミノフェニルチオ基、２－ヒドロキシフェニルチオ基などが挙げられる。 Examples of the arylthio group include phenylthio group, 1-naphthylthio group, 2-naphthylthio group, 9-anthrylthio group, chlorophenylthio group, trifluoromethylphenylthio group, cyanophenylthio group, nitrophenylthio group, and 2-aminophenylthio group. , 2-hydroxyphenylthio group, etc.
上記で説明した基は、置換基を有していても良い。そのような置換基としては、ハロゲン原子や、シリル基、シアノ基、アミノ基や、前述の脂肪族炭化水素基、芳香族炭化水素基、アルコキシル基、アリ－ルオキシ基等が挙げられる。その他、骨格構造の一部が、エステル結合（－ＣＯＯ－）、エーテル結合（－Ｏ－）、アミド結合（－ＮＨＣＯ－）等の原子団に置換されていても良い。親水性の置換基は、近赤外蛍光色素が非水溶性を保つ範囲で含むことができる。 The group explained above may have a substituent. Examples of such substituents include halogen atoms, silyl groups, cyano groups, amino groups, the aforementioned aliphatic hydrocarbon groups, aromatic hydrocarbon groups, alkoxyl groups, and aryloxy groups. In addition, a part of the skeleton structure may be substituted with an atomic group such as an ester bond (-COO-), an ether bond (-O-), or an amide bond (-NHCO-). Hydrophilic substituents can be included as long as the near-infrared fluorescent dye maintains water-insolubility.
例えば、ＺのＲ１９、Ｒ２０、および、Ｒ２１における、置換基を有してもよいアルキル基としては、下記一般式（３）または一般式（４）に示される構造であってもよい。 For example, the alkyl group which may have a substituent in R 19, R 20, and R 21 of Z may have a structure shown in the following general formula (3) or general formula (4). .
一般式（３） －Ｒ４６－Ｘ１
一般式（４） －Ｒ４６－Ｘ２－Ｘ１
（一般式（３）および一般式（４）において、Ｒ４６は炭素数１～３のアルキレン基を表す。Ｘ１はアミノ基、またはカルボキシ基を表す。Ｘ２は、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ2－ＣＨ2－を表す。
General formula (3) -R 46 -X 1
General formula (4) -R 46 -X 2 -X 1
(In general formulas (3) and (4), R 46 represents an alkylene group having 1 to 3 carbon atoms. X 1 represents an amino group or a carboxy group. X 2 represents -NH-C (= O) -CH 2 -CH 2 -.
Ｍは、３価の金属原子としては、Ａｌ、Ｇａ、Ｉｎ等が挙げられる。４価の金属原子としては、Ｓｉ、Ｍｎ、Ｓｎ、Ｃｒ、Ｚｒ等が挙げられる。蛍光強度の観点からは、Ｍｇ、Ａｌ、Ｓｉ、Ｚｎが好ましい。 Examples of trivalent metal atoms for M include Al, Ga, and In. Examples of the tetravalent metal atoms include Si, Mn, Sn, Cr, and Zr. From the viewpoint of fluorescence intensity, Mg, Al, Si, and Zn are preferable.
（両親媒性物質）
両親媒性物質とは、一つの分子内に親水基と疎水基を有する分子の総称であり、代表的なものとして界面活性剤やリン脂質などがある。両親媒性物質は一種類のみを使用してもよく、二種類以上を混合して使用してもよい。本実施形態に関わる両親媒性物質としては、特に限定されることはなく、非水溶性の近赤外蛍光色素を水に可溶化することができればいかなるものでもよい。
(amphiphile)
Amphiphilic substances are a general term for molecules that have a hydrophilic group and a hydrophobic group in one molecule, and typical examples include surfactants and phospholipids. Only one type of amphipathic substance may be used, or a mixture of two or more types may be used. The amphiphilic substance related to this embodiment is not particularly limited, and any substance may be used as long as it can solubilize a water-insoluble near-infrared fluorescent dye in water.
界面活性剤としては、非イオン性界面活性剤、カチオン性界面活性剤、アニオン性界面活性剤、高分子界面活性剤などを挙げることができる。 Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants, and polymeric surfactants.
非イオン性界面活性剤としては、例えば、Ｔｗｅｅｎ（登録商標）２０、Ｔｗｅｅｎ（登録商標）４０、Ｔｗｅｅｎ（登録商標）６０、Ｔｗｅｅｎ（登録商標）８０などのポリオキシエチレンソルビタン系脂肪酸エステル、Ｃｒｅｍｏｐｈｏｒ（登録商標）ＥＬ、Ｃｒｅｍｏｐｈｏｒ（登録商標）ＲＨ６０などのポリオキシエチレンヒマシ油誘導体、Ｓｏｌｕｔｏｌ（登録商標）ＨＳ １５などの１２－ヒドロキシステアリン酸－ポリエチレングリコールコポリマー、Ｔｒｉｔｏｎ（登録商標）Ｘ－１００、Ｔｒｉｔｏｎ（登録商標）Ｘ－１１４などのオクチルフェノールエトキシレートなどを挙げることができる。 Examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid esters such as Tween (registered trademark) 20, Tween (registered trademark) 40, Tween (registered trademark) 60, and Tween (registered trademark) 80, Cremophor ( Polyoxyethylene castor oil derivatives such as (registered trademark) EL, Cremophor (registered trademark) RH60, 12-hydroxystearic acid-polyethylene glycol copolymers such as Solutol (registered trademark) HS 15, Triton (registered trademark) Examples include octylphenol ethoxylates such as (registered trademark) X-114.
カチオン性界面活性剤としては、例えば、塩化ステアリルトリメチルアンモニウム、塩化ラウリルトリメチルアンモニウムなどのアルキルトリメチルアンモニウム塩、塩化セチルピリジニウムなどのアルキルピリジニウム塩、塩化ジステアリルジメチルアンモニウム、ジアルキルジメチルアンモニウム塩、塩化ポリ（Ｎ，Ｎ’－ジメチル－３，５－メチレンピペリジニウム）などのアルキル四級アンモニウム塩、アルキルジメチルベンジルアンモニウム塩、アルキルイソキノリニウム塩、ジアルキルモリホニウム塩、ポリオキシエチレンアルキルアミン、アルキルアミン塩、ポリアミン脂肪酸誘導体、アミルアルコール脂肪酸誘導体、塩化ベンザルコニウム、塩化ベンゼトニウムなどを挙げることができる。 Examples of cationic surfactants include alkyltrimethylammonium salts such as stearyltrimethylammonium chloride and lauryltrimethylammonium chloride, alkylpyridinium salts such as cetylpyridinium chloride, distearyldimethylammonium chloride, dialkyldimethylammonium salts, poly(N , N'-dimethyl-3,5-methylenepiperidinium), alkyl quaternary ammonium salts, alkyldimethylbenzylammonium salts, alkylisoquinolinium salts, dialkylmorphonium salts, polyoxyethylenealkylamines, alkylamines Examples include salts, polyamine fatty acid derivatives, amyl alcohol fatty acid derivatives, benzalkonium chloride, benzethonium chloride, and the like.
アニオン性界面活性剤としては、例えば、ドデシル硫酸ナトリウム、ドデシルベンゼンスルホネート、デシルベンゼンスルホネート、ウンデシルベンゼンスルホネート、トリデシルベンゼンスルホネート、ノニルベンゼンスルホネート並びにこれらのナトリウム、カリウム及びアンモニウム塩などが挙げられる。 Examples of the anionic surfactant include sodium dodecyl sulfate, dodecylbenzenesulfonate, decylbenzenesulfonate, undecylbenzenesulfonate, tridecylbenzenesulfonate, nonylbenzenesulfonate, and their sodium, potassium, and ammonium salts.
高分子界面活性剤としては、例えば、ポリビニルアルコール、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール－ポリアルキル、ポリエチレングリコール－ポリ乳酸、ポリエチレングリコール－ポリカプロラクトン、ポリエチレングリコール－ポリグリコール酸、ポリエチレングリコール－ポリ（ラクチド－グリコリド）などのブロック共重合体を挙げることができる。ポリオキシエチレンポリオキシプロピレングリコールの市販品としては、プルロニックＦ６８（ＢＡＳＦ社製）、プルロニックＦ１２７（ＢＡＳＦ社製）等が挙げられる。 Examples of polymeric surfactants include polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol, polyethylene glycol-polyalkyl, polyethylene glycol-polylactic acid, polyethylene glycol-polycaprolactone, polyethylene glycol-polyglycolic acid, polyethylene glycol-poly Examples include block copolymers such as (lactide-glycolide). Commercially available polyoxyethylene polyoxypropylene glycols include Pluronic F68 (manufactured by BASF) and Pluronic F127 (manufactured by BASF).
リン脂質としては、ジステアロイルホスファチジルコリン（ＤＳＰＣ）、ジミリストリルホスファチジルコリン（ＤＭＰＣ）、ジパルミトイルホスファチジルコリン（ＤＰＰＣ）、ジオレイルホスファチジルコリン（ＤＯＰＣ）、ジパルミトイルホスファチジルグリセロール（ＤＰＰＧ）などの合成リン脂質、ホスファチジルコリン、ホスファチジルセリン、ホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルエタノールアミン、ホスファチジン酸、カルジオリピン、スフィンゴミエリン、卵黄レシチン、大豆レシチン、リゾレシチンなどの天然リン脂質を挙げることができる。 Examples of phospholipids include synthetic phospholipids such as distearoyl phosphatidylcholine (DSPC), dimyristrylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dioleyl phosphatidylcholine (DOPC), dipalmitoylphosphatidylglycerol (DPPG), phosphatidylcholine, and phosphatidyl. Mention may be made of natural phospholipids such as serine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, cardiolipin, sphingomyelin, egg yolk lecithin, soybean lecithin, lysolecithin.
（近赤外蛍光組成物の組成割合）
本発明における近赤外蛍光組成物は、上記の近赤外蛍光色素と、上記の両親媒性物質と、水とを含む。そして近赤外蛍光色素は、両親媒性物質を含む水溶液中で可溶化された状態で存在する。近赤外蛍光色素の濃度は特に限定されないが、例えば、細胞を扱う場合、細胞の機能障害や増殖阻害などへの影響を考量すると、濃度は低い方が好ましく、近赤外蛍光色素の濃度は１００μＭ以下であることが好ましい。ただし、近赤外蛍光色素の濃度が低過ぎると、蛍光を認識することが難しいため、１μＭ以上であることが好ましい。また同様に、両親媒性物質の濃度も低い方が好ましく、両親媒性物質の量は、近赤外蛍光色素に対して５００倍質量部以下が好ましく、２００倍質量部以下がより好ましく、１００倍質量部以下がさらに好ましい。ただし、両親媒性物質の量が少な過ぎると、近赤外蛍光色素の会合や凝集が生じる恐れがあるため、近赤外蛍光色素に対して１０倍質量部以上の量であることが好ましい。
(Composition ratio of near-infrared fluorescent composition)
The near-infrared fluorescent composition in the present invention contains the above-mentioned near-infrared fluorescent dye, the above-mentioned amphipathic substance, and water. The near-infrared fluorescent dye exists in a solubilized state in an aqueous solution containing an amphipathic substance. The concentration of the near-infrared fluorescent dye is not particularly limited, but for example, when handling cells, considering the effects on cell dysfunction and growth inhibition, the lower the concentration is, the more preferable the concentration of the near-infrared fluorescent dye is. It is preferably 100 μM or less. However, if the concentration of the near-infrared fluorescent dye is too low, it will be difficult to recognize the fluorescence, so it is preferably 1 μM or more. Similarly, the concentration of the amphipathic substance is preferably low, and the amount of the amphipathic substance is preferably 500 parts by mass or less, more preferably 200 parts by mass or less, and 100 parts by mass or less relative to the near-infrared fluorescent dye. More preferably, the amount is double parts by mass or less. However, if the amount of the amphiphilic substance is too small, association or aggregation of the near-infrared fluorescent dye may occur, so the amount is preferably 10 parts by mass or more relative to the near-infrared fluorescent dye.
（近赤外蛍光組成物の作製方法）
本発明における近赤外蛍光組成物の作製方法は、特に限定されないが、例えば、近赤外蛍光色素と両親媒性物質を有機溶媒中に溶解した後、有機溶媒を留去し、水に再溶解させる方法、あるいは近赤外蛍光色素と両親媒性物質を有機溶媒に溶解した溶液に水を注入し、有機溶媒を留去する方法などを挙げることができる。
(Method for producing near-infrared fluorescent composition)
The method for producing the near-infrared fluorescent composition in the present invention is not particularly limited, but for example, after dissolving the near-infrared fluorescent dye and the amphiphilic substance in an organic solvent, the organic solvent is distilled off and the composition is rehydrated in water. Examples include a method of dissolving, or a method of injecting water into a solution of a near-infrared fluorescent dye and an amphipathic substance dissolved in an organic solvent, and distilling off the organic solvent.
前者の方法では、有機溶媒の留去が容易であり、近赤外蛍光色素と両親媒性物質の濃度も比較的容易に見積もることができるといった利点がある。有機溶媒の留去には、エバポレーターなどによる減圧留去装置が好適に用いられる。溶媒留去時の温度は、１５℃から有機溶媒の沸点温度の範囲で任意に設定することができる。水に再溶解させるときは、プロペラ撹拌機、タービン撹拌機、ボルテックスミキサー、撹拌子を用いたマグネティックスターラーによる撹拌、あるいは超音波照射装置による分散などが好適に用いられる。また、コロイドミルなどを併用してもよい。 The former method has the advantage that the organic solvent can be easily distilled off, and the concentrations of the near-infrared fluorescent dye and amphiphile can be estimated relatively easily. A vacuum distillation device such as an evaporator is preferably used to remove the organic solvent. The temperature during solvent distillation can be arbitrarily set within the range of 15° C. to the boiling point temperature of the organic solvent. When redissolving in water, stirring with a propeller stirrer, turbine stirrer, vortex mixer, magnetic stirrer using a stirring bar, dispersion using an ultrasonic irradiation device, etc. are preferably used. Further, a colloid mill or the like may be used in combination.
後者の方法では、ミセル粒子を均一に調製し易いといった利点がある。有機溶媒に溶解した溶液に水を注入するとき、溶液は撹拌あるいは超音波照射した状態とし、水を短時間で注入することが好ましい。撹拌は上記と同様の装置で行うことができる。水注入時の温度は、１５℃から有機溶媒の沸点より５℃低い温度の範囲で任意に設定することができる。有機溶媒の留去は、撹拌あるいは超音波照射した状態で常圧の下に留去する方法、あるいはエバポレーターなどにより減圧留去する方法が好ましい。溶媒留去時の温度は、１５℃から有機溶媒の沸点温度の範囲で任意に設定することができる。 The latter method has the advantage that micelle particles can be easily prepared uniformly. When injecting water into a solution dissolved in an organic solvent, it is preferable that the solution be stirred or irradiated with ultrasonic waves, and the water be injected in a short period of time. Stirring can be performed using the same device as above. The temperature during water injection can be arbitrarily set within the range of 15°C to 5°C lower than the boiling point of the organic solvent. The organic solvent is preferably distilled off under normal pressure under stirring or ultrasonic irradiation, or under reduced pressure using an evaporator or the like. The temperature during solvent distillation can be arbitrarily set within the range of 15° C. to the boiling point temperature of the organic solvent.
上記の作製方法で使用される有機溶媒としては、ヘキサン、シクロへキサン、およびヘプタンなどの炭化水素類、アセトンおよびメチルエチルケトンなどのケトン類、ジエチルエーテルおよびテトラヒドロフランなどのエーテル類、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、およびトリクロロエタンなどのハロゲン化炭化水素類、ベンゼンおよびトルエンなどの芳香族炭化水素、酢酸エチルおよび酢酸ブチルなどのエステル類、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、およびＮ－メチル－２－ピロリドンなどの非プロトン性極性溶媒類、メタノール、エタノール、プロパノール、などのアルコール類、あるいはピリジン誘導体を挙げることができる。これらの溶媒は、単独で使用してもよく、混合して使用してもよい。
また、上記方法にて作製した組成物を透析にかけることで、有機溶媒を完全に除去してもよい。
Organic solvents used in the above preparation method include hydrocarbons such as hexane, cyclohexane, and heptane, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and tetrahydrofuran, dichloromethane, chloroform, and tetrachloride. Carbon, halogenated hydrocarbons such as dichloroethane, and trichloroethane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate and butyl acetate, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2 - Examples include aprotic polar solvents such as pyrrolidone, alcohols such as methanol, ethanol, propanol, and pyridine derivatives. These solvents may be used alone or in combination.
Alternatively, the organic solvent may be completely removed by subjecting the composition prepared by the above method to dialysis.
上記の作製方法で使用される水としては、イオン交換水、蒸留水、あるいは超純水を挙げることができる。細胞を扱う場合は、生理条件に近づけるために水に塩を加えた生理食塩水、さらにリン酸緩衝剤を加えたリン酸緩衝生理食塩水などを好適に用いることができる。 Examples of the water used in the above production method include ion exchange water, distilled water, and ultrapure water. When handling cells, physiological saline prepared by adding salt to water to approximate physiological conditions, phosphate buffered saline prepared by adding a phosphate buffer, etc. can be suitably used.
（近赤外蛍光標識剤）
本発明の近赤外蛍光標識剤の用途は特に限定されないが、例えば、タンパク質や生体内の低分子化合物を蛍光ラベルすることで、生体内での挙動を可視化することが挙げられる。
この用途の場合、近赤外蛍光色素と両親媒性物質からなる粒子に、ターゲット分子に結合する物質を修飾することが好ましい。ターゲット分子に結合する物質としては、ターゲット分子と特異的に結合する一次抗体、その一次抗体に結合する二次抗体、アビジン、ビオチン、あるいは糖鎖などが挙げられる。
(Near-infrared fluorescent labeling agent)
Although the use of the near-infrared fluorescent labeling agent of the present invention is not particularly limited, for example, fluorescent labeling of proteins or low molecular compounds in vivo may be used to visualize their behavior in vivo.
For this use, it is preferable to modify particles consisting of a near-infrared fluorescent dye and an amphiphilic substance with a substance that binds to a target molecule. Examples of the substance that binds to the target molecule include a primary antibody that specifically binds to the target molecule, a secondary antibody that binds to the primary antibody, avidin, biotin, sugar chains, and the like.
以下に、本発明を実施例に基づいて説明するが、本発明はこれによって限定されるものではない。なお、実施例中、「部」は「質量部」を、「％」は「質量％」をそれぞれ表す。 The present invention will be described below based on examples, but the present invention is not limited thereto. In the examples, "parts" and "%" represent "parts by mass" and "% by mass," respectively.
＜近赤外蛍光色素の合成例＞
［色素合成例１］
３－ニトロフタロニトリル１０部および２，４－ジメチル－３－ペンタノール７．４部をＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ）７０部に溶解し、この溶液に、別途調製したｔ－ブトキシナトリウム６．１部およびＤＭＦ４０部を含む溶液を、０℃以下の温度で滴下した。更に、８０％酢酸４．８部、塩酸１７．５部を加えた。更に、水７０部を滴下して生じた結晶を濾別し、得られた結晶を水で洗浄した後に乾燥して、３－（２’，４’－ジメチル－３’－ペントキシ）フタロニトリル１１．９部を得た。
キノリン６８部及び無水塩化アルミニウム２．２部の溶液にアンモニアガスを導入し、上記で得られた３－（２’，４’－ジメチル－３’－ペントキシ）フタロニトリル１１．９部を加えた。１８０℃に加熱して２時間反応した。これを室温（２５℃）まで冷却し結晶を析出させた。生じた結晶を濾別し、結晶を４７％メタノール水溶液で洗浄した後に乾燥して、アルミニウムフタロシアニン中間体１０．３部を得た。
このアルミニウムフタロシアン中間体１部を、２－ブタノン１０部中で、ジメチルフェニルクロロシラン０．２３部およびトリエチルアミン０．１４部と４５℃で２時間反応させた。生じた析出物を濾別し、得られた濾液にアセトンを２０部加え、さらにイオン交換水１５部を滴下することにより、結晶が析出した。析出した結晶を濾別し、６６％アセトン水溶液１５部で洗浄した後に乾燥して、フタロシアニン化合物（Ｄ－１）０．７部を得た。
ＭＳ分析および1Ｈ－ＮＭＲ分析の結果が下記の通りであることより、フタロシアニン化合物（Ｄ－１）であることを確認した。
ＭＳ分析による分子量：１１４６Ｄａ。
1Ｈ－ＮＭＲ分析（重クロロホルム：重ジメチルスルホキシド－ｄ6 質量比３：１ ＴＭＳ）によるピーク：９．１ｐｐｍ（４Ｈ、ｄ）、８．１ｐｐｍ（４Ｈ、ｔ）、７．７ｐｐｍ（４Ｈ，ｄ ）、６．５ｐｐｍ（１Ｈ、ｔ）、６．３ｐｐｍ（２Ｈ、ｔ）、５．１ｐｐｍ（２Ｈ、ｄ）、４．７ｐｐｍ（４Ｈ、ｔ）、２．６ｐｐｍ（８Ｈ、ｍ）、１．５ｐｐｍ（２４Ｈ，ｑ）、１．２ｐｐｍ（２４Ｈ、ｑ）、－２．４ｐｐｍ（６Ｈ、ｄ）。
<Example of synthesis of near-infrared fluorescent dye>
[Dye synthesis example 1]
10 parts of 3-nitrophthalonitrile and 7.4 parts of 2,4-dimethyl-3-pentanol were dissolved in 70 parts of N,N-dimethylformamide (DMF), and 6 parts of sodium t-butoxy prepared separately was added to this solution. A solution containing 1 part of DMF and 40 parts of DMF was added dropwise at a temperature below 0°C. Furthermore, 4.8 parts of 80% acetic acid and 17.5 parts of hydrochloric acid were added. Furthermore, 70 parts of water was added dropwise and the resulting crystals were filtered out, and the obtained crystals were washed with water and dried to obtain 3-(2',4'-dimethyl-3'-pentoxy)phthalonitrile 11. .9 copies were obtained.
Ammonia gas was introduced into a solution of 68 parts of quinoline and 2.2 parts of anhydrous aluminum chloride, and 11.9 parts of 3-(2',4'-dimethyl-3'-pentoxy)phthalonitrile obtained above was added. . The mixture was heated to 180°C and reacted for 2 hours. This was cooled to room temperature (25°C) to precipitate crystals. The resulting crystals were filtered, washed with a 47% aqueous methanol solution, and then dried to obtain 10.3 parts of an aluminum phthalocyanine intermediate.
One part of this aluminum phthalocyanine intermediate was reacted with 0.23 parts of dimethylphenylchlorosilane and 0.14 parts of triethylamine in 10 parts of 2-butanone at 45° C. for 2 hours. The resulting precipitate was filtered off, 20 parts of acetone was added to the resulting filtrate, and 15 parts of ion-exchanged water was added dropwise to precipitate crystals. The precipitated crystals were filtered, washed with 15 parts of a 66% acetone aqueous solution, and then dried to obtain 0.7 parts of phthalocyanine compound (D-1).
From the results of MS analysis and 1 H-NMR analysis as shown below, it was confirmed that it was a phthalocyanine compound (D-1).
Molecular weight by MS analysis: 1146 Da.
1 H-NMR analysis (deuterochloroform: deuterium dimethyl sulfoxide-d 6 mass ratio 3:1 TMS) peaks: 9.1 ppm (4H, d), 8.1 ppm (4H, t), 7.7 ppm (4H, d ), 6.5ppm (1H, t), 6.3ppm (2H, t), 5.1ppm (2H, d), 4.7ppm (4H, t), 2.6ppm (8H, m), 1.5ppm (24H, q), 1.2 ppm (24 H, q), -2.4 ppm (6H, d).
［色素合成例２］
スルホラン１２０部、１，８－ジアザビシクロ［５，４，０］－７－ウンデセン（ＤＢＵ）１４部に４－（２，２－ビス（トリフルオロメチル）プロピル）オキシ－１，３－ジイミノイソインドリン１０部および四塩化珪素５部を加え、１６０～１７０℃で８時間加熱撹拌後、冷却し、３５％塩酸８０部と水１５００部の混合溶液に注入撹拌し、８０℃で２時間加熱撹拌した。その後、析出した沈澱を濾別して、メタノール：水（質量比４：１）混合溶液で洗浄後、乾燥して、粗製シリコンフタロシアニン中間体１０部を得た。
この粗製シリコンフタロシアニン中間体を濃硫酸２５０部に溶解した後、氷水２０００部に注入し、析出した沈澱を濾別して、水洗後、乾燥して、シリコンフタロシアニン中間体９部を得た。この中間体５部をピリジン１００部、トリ－ｎ－ブチルアミン２５部に撹拌溶解した後、冷却しながらクロロジフェニルホスフィン１０部を加え、１１０℃で２時間加熱撹拌した後、冷却し、氷水１０００部中に注入した。析出した沈澱を濾別し、水洗後、乾燥して、フタロシアニン化合物（Ｄ－２）４部を得た。ＭＳ分析および1Ｈ－ＮＭＲ分析より、フタロシアニン化合物（Ｄ－２）であることを確認した。
[Dye synthesis example 2]
120 parts of sulfolane, 14 parts of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and 4-(2,2-bis(trifluoromethyl)propyl)oxy-1,3-diiminoiso Add 10 parts of indoline and 5 parts of silicon tetrachloride, heat and stir at 160-170°C for 8 hours, cool, pour into a mixed solution of 80 parts of 35% hydrochloric acid and 1500 parts of water, stir, and heat and stir at 80°C for 2 hours. did. Thereafter, the deposited precipitate was separated by filtration, washed with a mixed solution of methanol:water (mass ratio 4:1), and then dried to obtain 10 parts of a crude silicon phthalocyanine intermediate.
This crude silicon phthalocyanine intermediate was dissolved in 250 parts of concentrated sulfuric acid, then poured into 2000 parts of ice water, and the precipitate was filtered, washed with water, and dried to obtain 9 parts of a silicon phthalocyanine intermediate. After stirring and dissolving 5 parts of this intermediate in 100 parts of pyridine and 25 parts of tri-n-butylamine, 10 parts of chlorodiphenylphosphine was added while cooling, and the mixture was heated and stirred at 110°C for 2 hours, cooled, and dissolved in 1000 parts of ice water. Injected inside. The deposited precipitate was separated by filtration, washed with water, and dried to obtain 4 parts of phthalocyanine compound (D-2). It was confirmed by MS analysis and 1 H-NMR analysis that it was a phthalocyanine compound (D-2).
［色素合成例３］
ｏ－ジクロロベンゼン５０部、トリ－ｎ－ブチルアミン２５部に、４－（２，２－ビス（トリフルオロメチル）プロピル）オキシ－１，３－ジイミノイソインドリン８部および四塩化珪素６部を加え、１６０～１７０℃で７時間加熱撹拌後、冷却し、メタノール１０００部で希釈後、析出した沈澱を濾別して、メタノール：水（質量比３：１）混合溶液で洗浄後、乾燥して、粗製アルミニウムフタロシアニン中間体５．５部を得た。
この粗製アルミニウムフタロシアニン中間体を濃硫酸３００部に溶解した後、氷水６０００部に注入し、析出した沈澱を濾別して、水洗後、乾燥して、アルミニウムフタロシアニン中間体４．３部を得た。この中間体４部をピリジン８０部、トリ－ｎ－ブチルアミン２０部に撹拌溶解した後、冷却しながらクロロジフェニルホスフィン５部を加え、１１０℃で２時間加熱撹拌した後、冷却し、氷水１０００部に注入した。析出した沈澱を濾別し、水洗後、乾燥して、フタロシアニン化合物（Ｄ－３）３．５部を得た。ＭＳ分析および1Ｈ－ＮＭＲ分析より、フタロシアニン化合物（Ｄ－３）であることを確認した。
[Dye synthesis example 3]
To 50 parts of o-dichlorobenzene and 25 parts of tri-n-butylamine, 8 parts of 4-(2,2-bis(trifluoromethyl)propyl)oxy-1,3-diiminoisoindoline and 6 parts of silicon tetrachloride were added. In addition, after heating and stirring at 160 to 170 ° C. for 7 hours, cooling, diluting with 1000 parts of methanol, and filtering out the precipitate, washing with a methanol:water (mass ratio 3:1) mixed solution, and drying. 5.5 parts of a crude aluminum phthalocyanine intermediate was obtained.
This crude aluminum phthalocyanine intermediate was dissolved in 300 parts of concentrated sulfuric acid, then poured into 6,000 parts of ice water, and the precipitate was filtered, washed with water, and dried to obtain 4.3 parts of an aluminum phthalocyanine intermediate. After stirring and dissolving 4 parts of this intermediate in 80 parts of pyridine and 20 parts of tri-n-butylamine, 5 parts of chlorodiphenylphosphine was added while cooling, and the mixture was heated and stirred at 110°C for 2 hours, cooled, and dissolved in 1000 parts of ice water. injected into. The deposited precipitate was separated by filtration, washed with water, and dried to obtain 3.5 parts of phthalocyanine compound (D-3). It was confirmed by MS analysis and 1 H-NMR analysis that it was a phthalocyanine compound (D-3).
［色素合成例４］
色素合成例２で得られたシリコンフタロシアニン中間体１部を、２－ブタノン１０部中で、トリフェニルクロロシラン０．５部およびトリエチルアミン０．３部と４５℃で５時間反応させた。生じた析出物を濾別し、得られた濾液にアセトンを２０部加え、さらにイオン交換水１５部を滴下することにより、結晶が析出した。析出した結晶を濾別し、６６％アセトン水溶液１５部で洗浄した後に乾燥して、フタロシアニン化合物（Ｄ－４）０．８部を得た。ＭＳ分析および1Ｈ－ＮＭＲ分析の結果が下記の通りであることより、フタロシアニン化合物（Ｄ－４）であることを確認した。
[Dye synthesis example 4]
One part of the silicon phthalocyanine intermediate obtained in Dye Synthesis Example 2 was reacted with 0.5 parts of triphenylchlorosilane and 0.3 parts of triethylamine at 45° C. for 5 hours in 10 parts of 2-butanone. The resulting precipitate was filtered off, 20 parts of acetone was added to the resulting filtrate, and 15 parts of ion-exchanged water was added dropwise to precipitate crystals. The precipitated crystals were separated by filtration, washed with 15 parts of a 66% acetone aqueous solution, and then dried to obtain 0.8 parts of phthalocyanine compound (D-4). From the results of MS analysis and 1 H-NMR analysis as shown below, it was confirmed that it was a phthalocyanine compound (D-4).
［色素合成例５］
ｎ－アミルアルコール１２．５部にフタロジニトリル２．３部と塩化アルミニウム無水物７８部を混合攪拌した。これに、ＤＢＵ２．７部を加え、昇温し、１３６℃で５時間還流した。攪拌したまま３０℃まで冷却した反応溶液を、メタノール５０部、水１００部からなる混合溶媒中へ攪拌しながら注入し、青色のスラリーを得た。このスラリーを濾過して、メタノール２０部、水４０部からなる混合溶媒で洗浄し、乾燥して、１．４部のクロロアルミニウムフタロシアニンを得た。次いで、濃硫酸１２部に得られたクロロアルミニウムフタロシアニン１部を室温（２５℃）にて加えた。４０℃、３時間撹拌した後、３℃の冷水２４０部にこの硫酸溶液を注入し、析出物をろ過、水洗後、乾燥して、０．９部のヒドロキシアルミニウムフタロシアニン（Ｄ－５）を得た。
元素分析結果が下記の通りであることより、ヒドロキシアルミニウムフタロシアニン（Ｄ－５）であることを確認した。
計算値（Ｃ）６９．０６％、（Ｈ）３．０８％、（Ｎ）２０．１４％
実測値（Ｃ）６９．１％、（Ｈ）３．２％、（Ｎ）２０．１％
[Dye synthesis example 5]
12.5 parts of n-amyl alcohol, 2.3 parts of phthalodinitrile and 78 parts of aluminum chloride anhydride were mixed and stirred. To this, 2.7 parts of DBU was added, the temperature was raised, and the mixture was refluxed at 136°C for 5 hours. The reaction solution, which had been cooled to 30° C. while being stirred, was poured into a mixed solvent consisting of 50 parts of methanol and 100 parts of water, with stirring, to obtain a blue slurry. This slurry was filtered, washed with a mixed solvent consisting of 20 parts of methanol and 40 parts of water, and dried to obtain 1.4 parts of chloroaluminum phthalocyanine. Next, 1 part of the obtained chloroaluminum phthalocyanine was added to 12 parts of concentrated sulfuric acid at room temperature (25°C). After stirring at 40°C for 3 hours, this sulfuric acid solution was poured into 240 parts of cold water at 3°C, and the precipitate was filtered, washed with water, and dried to obtain 0.9 parts of hydroxyaluminum phthalocyanine (D-5). Ta.
From the elemental analysis results as shown below, it was confirmed that it was hydroxyaluminum phthalocyanine (D-5).
Calculated values (C) 69.06%, (H) 3.08%, (N) 20.14%
Actual value (C) 69.1%, (H) 3.2%, (N) 20.1%
［色素合成例６］
３－ニトロフタロニトリル１０部および２，４－ジメチル－３－ペンタノール７．４部をＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ）７０部に溶解し、この溶液に、別途調製したｔ－ブトキシナトリウム６．１部およびＤＭＦ４０部を含む溶液を、０℃以下の温度で滴下した。更に、８０％酢酸４．８部、塩酸１７．５部を加えた。更に、水７０部を滴下して生じた結晶を濾別し、得られた結晶を水で洗浄した後に乾燥して、３－（２’，４’－ジメチル－３’－ペントキシ）フタロニトリル１１．９部を得た。
キノリン６８部及び無水塩化アルミニウム２．２部の溶液にアンモニアガスを導入し、上記で得られた３－（２’，４’－ジメチル－３’－ペントキシ）フタロニトリル１１．９部を加えた。１８０℃に加熱して２時間反応した。これを室温（２５℃）まで冷却し結晶を析出させた。生じた結晶を濾別し、結晶を４７％メタノール水溶液で洗浄した後に乾燥して、アルミニウムフタロシアニン中間体１０．３部を得た。
このアルミニウムフタロシアン中間体１部を、２－ブタノン１０部中で、トリフェニルクロロシラン０．２３部およびトリエチルアミン０．１４部と４５℃で２時間反応させた。生じた析出物を濾別し、得られた濾液にアセトンを２０部加え、さらにイオン交換水１５部を滴下することにより、結晶が析出した。析出した結晶を濾別し、６６％アセトン水溶液１５部で洗浄した後に乾燥して、フタロシアニン化合物（Ｄ－６）０．７部を得た。
ＭＳ分析および1Ｈ－ＮＭＲ分析より、フタロシアニン化合物（Ｄ－６）であることを確認した。
ＭＳ分析による分子量：１２７１Ｄａ。
[Dye synthesis example 6]
10 parts of 3-nitrophthalonitrile and 7.4 parts of 2,4-dimethyl-3-pentanol were dissolved in 70 parts of N,N-dimethylformamide (DMF), and 6 parts of sodium t-butoxy prepared separately was added to this solution. A solution containing 1 part of DMF and 40 parts of DMF was added dropwise at a temperature below 0°C. Furthermore, 4.8 parts of 80% acetic acid and 17.5 parts of hydrochloric acid were added. Furthermore, 70 parts of water was added dropwise and the resulting crystals were filtered out, and the obtained crystals were washed with water and dried to obtain 3-(2',4'-dimethyl-3'-pentoxy)phthalonitrile 11. .9 copies were obtained.
Ammonia gas was introduced into a solution of 68 parts of quinoline and 2.2 parts of anhydrous aluminum chloride, and 11.9 parts of 3-(2',4'-dimethyl-3'-pentoxy)phthalonitrile obtained above was added. . The mixture was heated to 180°C and reacted for 2 hours. This was cooled to room temperature (25°C) to precipitate crystals. The resulting crystals were filtered, washed with a 47% aqueous methanol solution, and then dried to obtain 10.3 parts of an aluminum phthalocyanine intermediate.
One part of this aluminum phthalocyanine intermediate was reacted with 0.23 parts of triphenylchlorosilane and 0.14 parts of triethylamine in 10 parts of 2-butanone at 45° C. for 2 hours. The resulting precipitate was filtered off, 20 parts of acetone was added to the resulting filtrate, and 15 parts of ion-exchanged water was added dropwise to precipitate crystals. The precipitated crystals were filtered, washed with 15 parts of a 66% acetone aqueous solution, and then dried to obtain 0.7 parts of phthalocyanine compound (D-6).
It was confirmed by MS analysis and 1 H-NMR analysis that it was a phthalocyanine compound (D-6).
Molecular weight by MS analysis: 1271 Da.
［色素合成例７］
３－ニトロフタロニトリル２０部をジメチルアセトアミド１５０部に溶解させ、エタノール８部を添加した。そこに、ナトリウムエトキシド１２部をジメチルアセトアミド５０部に懸濁させた液を氷浴中で滴下ロートにて添加し８０℃で4時間反応させた。水７００部を加え、析出物をろ過によりフタロシアニン化合物（Ｄ－７）の原料となる３－エトキシフタロニトリルを１４部得た。
次に、窒素雰囲気下５０℃で、無水塩化アルミニウム １．３部をキノリン４０部に溶解させた後、アンモニアガスを１．５時間バブリングさせた。その後、３－エトキシフタロニトリルを５部加え、１８０℃６時間反応させた。反応液にメタノール２００部と水８５部、３５％塩酸６０部 を添加し、1時間攪拌後析出物をろ過して、クロロアルミニウムフタロシアニン中間体を５部得た。
クロロアルミニウムフタロシアニン中間体３．５部をＮ―メチルピロリドン５０部に溶解させた後、水酸化カリウム０．５４部を加え、５０℃で２時間反応させた。水１０００部を加え、１時間攪拌後析出物をろ過して、ヒドロキシアルミニウムフタロシアニン中間体を３部得た。
ヒドロキシアルミニウムフタロシアニン中間体２部をピリジン２５部に溶解させた後、３－アミノプロピルジメチルエトキシシラン１．１部加え、室温で一晩反応させた。エバポレーターでピリジンを除去した後、固形物をエタノール３０部に半溶解させ、水80部を加え、析出物をろ過、乾燥して、中間体である３－アミノプロピルジメチルエトキシシリルアルミフタロシアニン化合物０．８部を得た。
色素合成例７で得られた３－アミノプロピルジメチルエトキシシリルルアルミフタロシアニン中間体０．５部をNMPに溶解させた後、無水コハク酸０．０１２部を加え、９０℃で４時間反応させた。ＭＳ分析より、目的物の生成と、原料ピークの消失を確認した。水５０部と食塩を２０部加え、１．５時間攪拌させた後、遠心分離機(３０００rpm,５分)より固体を沈降させ濾別し、乾燥させ、フタロシアニン化合物（Ｄ－７）０．４部を得た。
ＭＳ分析および1Ｈ－ＮＭＲ分析より、フタロシアニン化合物（Ｄ－７）であることを確認した。
[Dye synthesis example 7]
20 parts of 3-nitrophthalonitrile was dissolved in 150 parts of dimethylacetamide, and 8 parts of ethanol were added. A solution prepared by suspending 12 parts of sodium ethoxide in 50 parts of dimethylacetamide was added thereto using a dropping funnel in an ice bath, and the mixture was reacted at 80°C for 4 hours. 700 parts of water was added, and the precipitate was filtered to obtain 14 parts of 3-ethoxyphthalonitrile, which is a raw material for phthalocyanine compound (D-7).
Next, 1.3 parts of anhydrous aluminum chloride was dissolved in 40 parts of quinoline at 50° C. under a nitrogen atmosphere, and then ammonia gas was bubbled for 1.5 hours. Thereafter, 5 parts of 3-ethoxyphthalonitrile was added and reacted at 180°C for 6 hours. 200 parts of methanol, 85 parts of water, and 60 parts of 35% hydrochloric acid were added to the reaction solution, and after stirring for 1 hour, the precipitate was filtered to obtain 5 parts of chloroaluminum phthalocyanine intermediate.
After dissolving 3.5 parts of chloroaluminum phthalocyanine intermediate in 50 parts of N-methylpyrrolidone, 0.54 parts of potassium hydroxide was added and the mixture was reacted at 50°C for 2 hours. 1000 parts of water was added, and after stirring for 1 hour, the precipitate was filtered to obtain 3 parts of a hydroxyaluminum phthalocyanine intermediate.
After 2 parts of the hydroxyaluminum phthalocyanine intermediate was dissolved in 25 parts of pyridine, 1.1 parts of 3-aminopropyldimethylethoxysilane was added, and the mixture was reacted overnight at room temperature. After removing pyridine with an evaporator, the solid matter was semi-dissolved in 30 parts of ethanol, 80 parts of water was added, the precipitate was filtered and dried, and the intermediate 3-aminopropyldimethylethoxysilylaluminum phthalocyanine compound was obtained with 0. I got 8 copies.
After dissolving 0.5 part of the 3-aminopropyldimethylethoxysilylaluminum phthalocyanine intermediate obtained in Dye Synthesis Example 7 in NMP, 0.012 part of succinic anhydride was added, and the mixture was reacted at 90°C for 4 hours. . MS analysis confirmed the production of the target product and the disappearance of the raw material peak. After adding 50 parts of water and 20 parts of common salt and stirring for 1.5 hours, the solid was precipitated using a centrifuge (3000 rpm, 5 minutes), filtered out, and dried to obtain 0.4 phthalocyanine compound (D-7). I got the department.
It was confirmed by MS analysis and 1 H-NMR analysis that it was a phthalocyanine compound (D-7).
＜近赤外蛍光色素のＴｗｅｅｎ ８０による可溶化液の調製例＞
［近赤外蛍光色素：Ｔｗｅｅｎ ８０＝１：５０（質量比）の調製例］
Ｔｗｅｅｎ８０（東京化成工業社製）とアセトンの１：１（質量比）混合溶液を１００部調製し、この溶液に近赤外蛍光色素１部を加えて完全溶解した。溶解しにくい場合は、適当量のアセトンを追加した。次いで、エバポレーターにてアセトンを減圧留去し、真空乾燥を１２時間行って、近赤外蛍光色素とＴｗｅｅｎ８０の均一混合物を得た。得られた混合物に超純水２０００部を加え、室温（２５℃）で撹拌溶解して、色素濃度０．０５％の溶液を得た。
<Example of preparation of solubilized solution using near-infrared fluorescent dye Tween 80>
[Preparation example of near-infrared fluorescent dye: Tween 80=1:50 (mass ratio)]
100 parts of a 1:1 (mass ratio) mixed solution of Tween 80 (manufactured by Tokyo Chemical Industry Co., Ltd.) and acetone was prepared, and 1 part of a near-infrared fluorescent dye was added to this solution to completely dissolve it. If it was difficult to dissolve, an appropriate amount of acetone was added. Next, acetone was distilled off under reduced pressure using an evaporator, and vacuum drying was performed for 12 hours to obtain a homogeneous mixture of near-infrared fluorescent dye and Tween 80. 2000 parts of ultrapure water was added to the resulting mixture, and the mixture was stirred and dissolved at room temperature (25°C) to obtain a solution with a dye concentration of 0.05%.
［近赤外蛍光色素：Ｔｗｅｅｎ ８０＝１：５００（質量比）の調製例］
近赤外蛍光色素を０．１部、超純水を２００部に変更した以外は、前述と同様な方法により、色素濃度０．０５％の溶液を得た。
[Preparation example of near-infrared fluorescent dye: Tween 80=1:500 (mass ratio)]
A solution with a dye concentration of 0.05% was obtained in the same manner as described above, except that the near-infrared fluorescent dye was changed to 0.1 part and the ultrapure water was changed to 200 parts.
＜モル吸光係数測定＞
上記の近赤外蛍光色素およびＴｗｅｅｎ ８０を含む各溶液を、超純水で希釈して色素濃度1～５０μＭの範囲内で数点の希釈溶液を調製し、各々の希釈溶液について、分光光度計（日立ハイテクノロジーズ社製、Ｕ－４１００）を用いてそれぞれ吸収スペクトルを測定した。そして、ランバート・ベールの法則に基づいて、最大吸収波長（λｍａｘ）におけるモル吸光係数（ε）を求めた。
<Molar extinction coefficient measurement>
Each solution containing the above near-infrared fluorescent dye and Tween 80 was diluted with ultrapure water to prepare several diluted solutions within the dye concentration range of 1 to 50 μM, and each diluted solution was measured using a spectrophotometer. (manufactured by Hitachi High-Technologies, U-4100) was used to measure the absorption spectra of each. Then, the molar extinction coefficient (ε) at the maximum absorption wavelength (λmax) was determined based on the Lambert-Beer law.
＜絶対蛍光量子収率測定＞
絶対蛍光量子収率（Φ）は、λｍａｘを励起波長とし、λｍａｘにおける吸光度が０．２０～０．３０の範囲内である希釈溶液について、絶対ＰＬ量子収率測定装置（浜松ホトニクス社製、Ｃ９９２０－０２）を用いて測定した。
<Absolute fluorescence quantum yield measurement>
The absolute fluorescence quantum yield (Φ) is measured using an absolute PL quantum yield measuring device (manufactured by Hamamatsu Photonics Co., Ltd., C9920) for a dilute solution whose excitation wavelength is λmax and the absorbance at λmax is within the range of 0.20 to 0.30. -02).
＜近赤外蛍光組成物の作製＞
［実施例１－１］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－１）１部、両親媒性物質としてポリエチレングリコール（ＰＥＧ）・ポリカプロラクトン（ＰＣＬ）ブロック共重合体（シグマアルドリッチ社製、ＰＥＧ分子量５０００、ＰＣＬ分子量５０００）１００部をアセトン２００００部に溶解した。得られたアセトン溶液を室温（２５℃）で撹拌下、超純水２５０００部を滴下した。さらに、室温（２５℃）で１２時間撹拌した後、アセトンを留去し、０．４５μｍナイロン製メンブレンフィルターで濾過し、フタロシアニン化合物（Ｄ－１）がＰＥＧ－ＰＣＬミセル内に可溶化された近赤外蛍光組成物を得た。このミセルの体積平均粒子径（以下、特に断りのない限り、単に「平均粒子径」と略記する）は、動的光散乱式ナノトラック粒度分布計（日機装社製、ＵＰＡ－ＥＸ１５０）を用いて測定したところ、５５ｎｍであった。
<Preparation of near-infrared fluorescent composition>
[Example 1-1]
1 part of phthalocyanine compound (D-1) as a near-infrared fluorescent dye, polyethylene glycol (PEG)/polycaprolactone (PCL) block copolymer as an amphipathic substance (manufactured by Sigma-Aldrich, PEG molecular weight 5000, PCL molecular weight 5000) 100 parts were dissolved in 20,000 parts of acetone. While stirring the obtained acetone solution at room temperature (25° C.), 25,000 parts of ultrapure water was added dropwise. Furthermore, after stirring at room temperature (25°C) for 12 hours, acetone was distilled off and filtered through a 0.45 μm nylon membrane filter. An infrared fluorescent composition was obtained. The volume average particle diameter (hereinafter simply referred to as "average particle diameter" unless otherwise specified) of the micelles was measured using a dynamic light scattering nanotrack particle size distribution analyzer (manufactured by Nikkiso Co., Ltd., UPA-EX150). When measured, it was 55 nm.
［実施例１－２］
両親媒性物質をポリエチレングリコール（ＰＥＧ）・ポリ乳酸（ＰＬＧＡ）ブロック共重合体（シグマアルドリッチ社製、ＰＥＧ分子量５０００、ＰＬＧＡ分子量７０００）に変更した以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、５０ｎｍであった。
[Example 1-2]
It was produced in the same manner as in Example 1-1, except that the amphiphilic substance was changed to a polyethylene glycol (PEG) polylactic acid (PLGA) block copolymer (manufactured by Sigma-Aldrich, PEG molecular weight 5000, PLGA molecular weight 7000). , a near-infrared fluorescent composition was obtained. The average particle diameter of the micelles was 50 nm.
［実施例２－１］
近赤外蛍光色素をフタロシアニン化合物（Ｄ－２）に変更した以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、５８ｎｍであった。
[Example 2-1]
A near-infrared fluorescent composition was obtained in the same manner as in Example 1-1 except that the near-infrared fluorescent dye was changed to phthalocyanine compound (D-2). The average particle diameter of the micelles was 58 nm.
［実施例２－２］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－２）０．１部、両親媒性物質として１，２－ジパルミトイル－ｓｎ－グリセロ－３－ホスホコリン（シグマアルドリッチ社製、ＤＰＰＣ）３部、１，２－ジパルミトイル－ｓｎ－グリセロ－３－ホスホ－ｒａｃ－（１－グリセロール）アンモニウム塩（シグマアルドリッチ社製、ＤＰＰＧ）０．８部およびコレステロール１．５部をクロロホルム６０部に溶解した。フラスコに移して、エバポレーターにてクロロホルムを減圧留去し、真空乾燥を１２時間行って、フラスコ底面にフタロシアニン化合物（Ｄ－２）と脂質の混合物の薄膜を形成させた。そのフラスコに超純水１００００部を添加し、６０℃超音波処理を行った。その後、０．２０μｍナイロン製メンブレンフィルターで濾過し、フタロシアニン化合物（Ｄ－２）がリポソーム内に可溶化された近赤外蛍光組成物を得た。このリポソームの平均粒子径は、動的光散乱式ナノトラック粒度分布計（日機装社製、ＵＰＡ－ＥＸ１５０）を用いて測定したところ、１５０ｎｍであった。
[Example 2-2]
0.1 part of a phthalocyanine compound (D-2) as a near-infrared fluorescent dye, 3 parts of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (manufactured by Sigma-Aldrich, DPPC), 1, 0.8 parts of 2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) ammonium salt (Sigma-Aldrich, DPPG) and 1.5 parts of cholesterol were dissolved in 60 parts of chloroform. The mixture was transferred to a flask, chloroform was distilled off under reduced pressure using an evaporator, and vacuum drying was performed for 12 hours to form a thin film of a mixture of phthalocyanine compound (D-2) and lipid on the bottom of the flask. 10,000 parts of ultrapure water was added to the flask, and ultrasonication was performed at 60°C. Thereafter, it was filtered through a 0.20 μm nylon membrane filter to obtain a near-infrared fluorescent composition in which the phthalocyanine compound (D-2) was solubilized within the liposome. The average particle diameter of this liposome was 150 nm when measured using a dynamic light scattering type Nanotrac particle size distribution analyzer (manufactured by Nikkiso Co., Ltd., UPA-EX150).
［実施例３－１］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－３）に変更した以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、６０ｎｍであった。
[Example 3-1]
A near-infrared fluorescent composition was obtained in the same manner as in Example 1-1 except that the near-infrared fluorescent dye was changed to phthalocyanine compound (D-3). The average particle diameter of the micelles was 60 nm.
［実施例４－１］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－４）に変更した以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、５５ｎｍであった。
[Example 4-1]
A near-infrared fluorescent composition was obtained in the same manner as in Example 1-1 except that the near-infrared fluorescent dye was changed to phthalocyanine compound (D-4). The average particle size of the micelles was 55 nm.
［実施例４－２］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－４）０．１部、両親媒性物質として、ポリオキシエチレンポリオキシプロピレングリコール（シグマアルドリッチ社製、プルロニックＦ-１２７）１００部をアセトン５００部、および水５００部に溶解し、６０℃で２時間超音波処理を行った。得られた色素溶液をフラスコへ移して、エバポレーターにてアセトンを減圧留去し、フラスコ底面にフタロシアニン化合物（Ｄ－４）と脂質の混合物の薄膜を形成させた。そのフラスコに超純水１００００部を添加し、８００ｒｐｍで撹拌処理を行った。その後、０．２０μｍナイロン製メンブレンフィルターで濾過し、フタロシアニン化合物（Ｄ－４）がミセル内に可溶化された近赤外蛍光組成物を得た。
このミセルの平均粒子径は、動的光散乱式ナノトラック粒度分布計（日機装社製、ＵＰＡ－ＥＸ１５０）を用いて測定したところ、７ｎｍであった。
[Example 4-2]
0.1 part of a phthalocyanine compound (D-4) as a near-infrared fluorescent dye, 100 parts of polyoxyethylene polyoxypropylene glycol (manufactured by Sigma-Aldrich, Pluronic F-127) as an amphipathic substance, 500 parts of acetone, and It was dissolved in 500 parts of water and subjected to ultrasonication at 60°C for 2 hours. The obtained dye solution was transferred to a flask, and acetone was distilled off under reduced pressure using an evaporator to form a thin film of a mixture of phthalocyanine compound (D-4) and lipid on the bottom of the flask. 10,000 parts of ultrapure water was added to the flask and stirred at 800 rpm. Thereafter, it was filtered through a 0.20 μm nylon membrane filter to obtain a near-infrared fluorescent composition in which the phthalocyanine compound (D-4) was solubilized in micelles.
The average particle diameter of the micelles was 7 nm when measured using a dynamic light scattering type Nanotrac particle size distribution analyzer (manufactured by Nikkiso Co., Ltd., UPA-EX150).
［実施例５－１］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－６）に変更した以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、５７ｎｍであった。
[Example 5-1]
A near-infrared fluorescent composition was obtained in the same manner as in Example 1-1 except that the near-infrared fluorescent dye was changed to phthalocyanine compound (D-6). The average particle diameter of the micelles was 57 nm.
［実施例５－２］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－６）に変更した以外は、実施例４－２と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、６ｎｍであった。
[Example 5-2]
A near-infrared fluorescent composition was obtained in the same manner as in Example 4-2 except that the near-infrared fluorescent dye was changed to phthalocyanine compound (D-6). The average particle diameter of the micelles was 6 nm.
［比較例１－１］
近赤外蛍光色素としてフタロシアニン化合物（Ｄ－５）に変更した以外は、実施例１－１と同様な方法で作製を試みたが、アセトンへの溶解性が低いため、近赤外蛍光組成物を得ることはできなかった。
[Comparative example 1-1]
Production was attempted in the same manner as in Example 1-1 except for changing the near-infrared fluorescent dye to a phthalocyanine compound (D-5), but due to its low solubility in acetone, the near-infrared fluorescent composition I couldn't get it.
［比較例２－１］
近赤外蛍光色素として亜鉛２，９，１６，２３－テトラ－ｔｅｒｔ－ブチル－２９Ｈ，３１Ｈ－フタロシアニン（ＴＴＢＺｎＰｃ、シグマアルドリッチ社製）を用いた以外は、実施例１－１と同様に作製し、近赤外蛍光組成物を得た。ミセルの平均粒子径は、５０ｎｍであった。
[Comparative example 2-1]
It was produced in the same manner as in Example 1-1, except that zinc 2,9,16,23-tetra-tert-butyl-29H,31H-phthalocyanine (TTBZnPc, manufactured by Sigma-Aldrich) was used as the near-infrared fluorescent dye. , a near-infrared fluorescent composition was obtained. The average particle diameter of the micelles was 50 nm.
＜近赤外蛍光標識剤としての評価＞
［細胞培養と蛍光顕微鏡観察］
ＨｅＬａ細胞を９６ウェルプレートに播種（５×１０3ｃｅｌｌ／ｗｅｌｌ）し、１０％Ｆｅｔａｌ Ｂｏｖｉｎｅ Ｓｅｒｕｍ（ＦＢＳ）および１％ペニシリン―ストレプトマイシンを含ませたＭｉｎｉｍｕｍ Ｅｓｓｅｎｔｉａｌ Ｍｅｄｉａ（ＭＥＭ）を用いて、インキュベーター（３７℃、５％ＣＯ2含有Ａｉｒ、加湿環境）内で２４時間培養した。その後、培地を取り除き、作製した各近赤外蛍光組成物を超純水で１０倍希釈したものを添加し、インキュベーター内に２４時間静置した後、リン酸緩衝食塩水（ＰＢＳ）で洗浄した。適切な波長の励起フィルターおよび蛍光フィルターを設置した蛍光顕微鏡（キーエンス社製、ＢＺ－Ｘ７１０）を用いて、細胞の暗視野像と蛍光像を観察した。それらの結果を表２に示す。実施例の近赤外蛍光組成物では蛍光ラベルされた細胞を明瞭に確認することができたが、比較例２－１では不明瞭であった。
<Evaluation as a near-infrared fluorescent labeling agent>
[Cell culture and fluorescence microscopy]
HeLa cells were seeded in a 96-well plate (5 x 10 3 cells/well) and incubated in an incubator (37°C) using Minimum Essential Media (MEM) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin. ℃, 5% CO 2 -containing air, humidified environment) for 24 hours. Thereafter, the medium was removed, and a 10-fold dilution of each prepared near-infrared fluorescent composition with ultrapure water was added, and the mixture was left in an incubator for 24 hours, and then washed with phosphate buffered saline (PBS). . Dark field images and fluorescence images of the cells were observed using a fluorescence microscope (Keyence Corporation, BZ-X710) equipped with excitation filters and fluorescence filters of appropriate wavelengths. The results are shown in Table 2. In the near-infrared fluorescent composition of Example, fluorescently labeled cells could be clearly confirmed, but in Comparative Example 2-1, they were unclear.
Claims (2)
式（１） （εａ×Φａ）／（εｂ×Φｂ）≧０．３
ただし、
εａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φａは、近赤外蛍光色素に対して５０倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素の絶対蛍光量子収率、
εｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素のモル吸光係数、
Φｂは、近赤外蛍光色素に対して５００倍質量のＴｗｅｅｎ ８０を含む水溶液中での近赤外蛍光色素の絶対蛍光量子収率、
を表す。 A near-infrared fluorescent composition comprising a near-infrared fluorescent dye, an amphiphilic substance, and water, wherein the near-infrared fluorescent dye is water-insoluble and has a maximum fluorescence wavelength of 700 nm or more. A near-infrared fluorescent composition , which is a phthalocyanine dye having a substituent having 17 or more atoms and having a trivalent or tetravalent central metal, which satisfies the following formula (1). thing.
Formula (1) (εa×Φa)/(εb×Φb)≧0.3
however,
εa is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
Φa is the absolute fluorescence quantum yield of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 50 times the mass of the near-infrared fluorescent dye;
εb is the molar extinction coefficient of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
Φb is the absolute fluorescence quantum yield of the near-infrared fluorescent dye in an aqueous solution containing Tween 80, which is 500 times the mass of the near-infrared fluorescent dye;
represents.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000352817A (en) | 1999-06-11 | 2000-12-19 | Fuji Photo Film Co Ltd | Photosensitive composition and lithographic printing original plate using it |
| JP2001270885A (en) | 2000-03-27 | 2001-10-02 | Toyo Ink Mfg Co Ltd | Method for manufacturing aluminum phthalocyanine |
| CN102416178A (en) | 2011-11-22 | 2012-04-18 | 福州大学 | Water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle |
| US20130008503A1 (en) | 2010-04-09 | 2013-01-10 | Mcgrath Dominic V | Organic photovoltaic devices comprising solution-processed substituted metal-phthalocyanines and exhibiting near-ir photo-sensitivity |
| JP2018513875A (en) | 2015-04-20 | 2018-05-31 | オレゴン ステート ユニヴァーシティ | Composition comprising a photosensitive compound in polymer nanoparticles and method of using the composition |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000352817A (en) | 1999-06-11 | 2000-12-19 | Fuji Photo Film Co Ltd | Photosensitive composition and lithographic printing original plate using it |
| JP2001270885A (en) | 2000-03-27 | 2001-10-02 | Toyo Ink Mfg Co Ltd | Method for manufacturing aluminum phthalocyanine |
| US20130008503A1 (en) | 2010-04-09 | 2013-01-10 | Mcgrath Dominic V | Organic photovoltaic devices comprising solution-processed substituted metal-phthalocyanines and exhibiting near-ir photo-sensitivity |
| CN102416178A (en) | 2011-11-22 | 2012-04-18 | 福州大学 | Water-soluble non-aggregated alkoxy-substituted phthalocyanine-silica nanometer particle |
| JP2018513875A (en) | 2015-04-20 | 2018-05-31 | オレゴン ステート ユニヴァーシティ | Composition comprising a photosensitive compound in polymer nanoparticles and method of using the composition |
Non-Patent Citations (1)
| Title |
|---|
| Ana C. S. Lobo，Journal of Medicinal Chemistry，2016年，59，4688-4696，DIO: 10.1021/acs.jmedchem.6b00054 |
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