JPH09309845A - Near-infrared fluorescent tracer and fluorescent imaging - Google Patents
Near-infrared fluorescent tracer and fluorescent imagingInfo
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- JPH09309845A JPH09309845A JP8149959A JP14995996A JPH09309845A JP H09309845 A JPH09309845 A JP H09309845A JP 8149959 A JP8149959 A JP 8149959A JP 14995996 A JP14995996 A JP 14995996A JP H09309845 A JPH09309845 A JP H09309845A
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- tracer
- infrared
- infrared fluorescent
- fluorescence
- dye
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、近赤外線蛍光トレ
ーサーに関する。TECHNICAL FIELD The present invention relates to a near infrared fluorescent tracer.
【０００２】[0002]
【従来の技術】厚みのある生体試料（人体等）の内部の
様子を光を使って体外計測する手法は、医学研究や疾病
の診断・治療にとって重要である。特に腫瘍の位置・大
きさを画像診断によって予め知る事は、腫瘍の摘出にと
って重要な技術であり、すでにいくつかの方法が知られ
ている。2. Description of the Related Art A method of measuring the inside of a thick biological sample (human body or the like) outside the body using light is important for medical research and diagnosis / treatment of diseases. In particular, knowing the position and size of a tumor in advance by image diagnosis is an important technique for tumor extraction, and several methods have already been known.
【０００３】例えば、放射性同位元素（ＲＩ）による腫
瘍組織や神経軸策流の画像診断は、被爆・汚染の懸念が
あり管理が煩雑であるという問題がある。また、管理区
域外では利用できないため、手術時への応用は難しいと
いう問題がある。例えば、神経筋接合部近傍に物質を投
与すると、神経細胞がその物質を取り込み、神経終端か
ら細胞体に向かって能動的に運搬する現象（神経軸策
流）が知られており、神経軸策流のスピードが正常に比
べ低下している場合は、その神経細胞に何らかの障害が
あると診断できることが知られている。実際、この診断
にＲＩを用いる試みがなされているが、腫瘍の診断と同
様の問題点を有している。For example, image diagnosis of tumor tissue and nerve axillary flow by radioisotope (RI) has a problem that there is a risk of exposure and contamination and management is complicated. In addition, since it cannot be used outside the control area, it is difficult to apply it during surgery. For example, it is known that when a substance is administered near the neuromuscular junction, the nerve cell takes in the substance and actively transports it from the nerve terminal toward the cell body (nerve axis trick flow). It is known that if the flow speed is lower than normal, it can be diagnosed that the nerve cell has some kind of disorder. In fact, attempts have been made to use RI for this diagnosis, but they have the same problems as those for tumor diagnosis.
【０００４】またＸ線ＣＴ技術は、被爆の問題は放射性
同位元素の場合と同様であり、また、装置が大型であ
り、被験者を断層撮影装置の奥まった内部に置かなけれ
ばならないので、手術時への応用は難しいという問題も
ある。Further, in the X-ray CT technique, the problem of exposure is similar to that in the case of radioactive isotope, and since the device is large in size, the subject must be placed inside the tomography device. There is also a problem that it is difficult to apply to.
【０００５】[0005]
【発明が解決しようとする課題】本発明は以上の問題点
に鑑みなされたものである。すなわち、厚みのある生体
試料（人体等）の内部の様子を近赤外蛍光により体外計
測するための毒性の低い生体に使用可能な新規トレーサ
ーを提供するものであり、また該トレーサーを用いた体
外計測イメージング法を提供するものである。The present invention has been made in view of the above problems. That is, the present invention provides a novel tracer that can be used for a living body with low toxicity for measuring the internal state of a thick biological sample (human body, etc.) by near-infrared fluorescence. It provides a metrology imaging method.
【０００６】[0006]
【課題を解決するための手段】近赤外光は生体への透過
性が高いため、近赤外蛍光を放つ色素を体内に分布させ
てその体外計測を行い、種々の診断等に応用することが
可能と考えられる。さらに、この方法においてはハロゲ
ンランプ、ＣＣＤカメラ、光学フィルターとレンズな
ど、小型で安価な装置のみの構成で実現できる。[Means for Solving the Problems] Since near-infrared light is highly transparent to living organisms, a dye that emits near-infrared fluorescence should be distributed in the body and measured in vitro to be applied to various diagnoses. Is considered possible. Further, this method can be realized with a configuration of only a small and inexpensive device such as a halogen lamp, a CCD camera, an optical filter and a lens.
【０００７】一方、色素については、トレーサーとして
生体に用いた場合はその毒性が問題になり、使用できる
色素に制限がある。この毒性の問題から、トレーサー色
素として使用可能なももの１つとしてインドシアニング
リーンが実際に臨床応用されている。この色素は有機溶
媒中で近赤外蛍光（８３５ｎｍ）を放ち、またこれを使
って眼底血管を蛍光観察した例がある。On the other hand, regarding the dye, when it is used as a tracer in the living body, its toxicity poses a problem, and there is a limit to the dye that can be used. Due to this toxicity problem, indocyanine green is actually clinically applied as one of the tracer dyes that can be used. This dye emits near-infrared fluorescence (835 nm) in an organic solvent, and there is an example of fluorescence observation of a fundus blood vessel using this dye.
【０００８】しかし、この色素は無極性溶媒（有機溶媒
等）中では蛍光性であるが、極性溶媒（水溶液等）中で
は無蛍光であり、上記の色素としてはこのままでは使用
できないものである。However, although this dye is fluorescent in a nonpolar solvent (organic solvent etc.), it is nonfluorescent in a polar solvent (aqueous solution etc.) and cannot be used as it is as the above dye.
【０００９】本発明者は以上の点に鑑み鋭意研究し、毒
性のない近赤外線蛍光色素を有し、しかも水溶性である
新規な近赤外線蛍光トレーサーを見出すことに成功し
た。すなわち、インドシアニングリーンのような毒性の
低い、しかし水溶液では実質的に蛍光性でない色素を適
当な高密度リポ蛋白質等と複合体を形成することによ
り、蛍光性となることを見出し、この知見に基づき上記
複合体を近赤外線蛍光トレーサーとすることに成功し
た。また被検出物を特異的に認識可能とする認識部をさ
らに有する近赤外線蛍光色素トレーサーを見出し、この
知見に基づき上記複合体を、被検出物を特異的に認識す
る近赤外線蛍光トレーサーとすることに成功した。The present inventor has conducted extensive studies in view of the above points and succeeded in finding a novel near-infrared fluorescent tracer having a non-toxic near-infrared fluorescent dye and being water-soluble. That is, it was found that by forming a complex with a high-density lipoprotein or the like having a low toxicity such as indocyanine green but not substantially fluorescent in an aqueous solution, it becomes fluorescent, and based on this finding, Based on this, we succeeded in using the above complex as a near infrared fluorescent tracer. In addition, a near-infrared fluorescent dye tracer further having a recognition unit capable of specifically recognizing an object to be detected has been found, and based on this finding, the complex is a near-infrared fluorescent tracer that specifically recognizes the object to be detected. succeeded in.
【００１０】より詳しくは、本発明は、少なくとも近赤
外線蛍光色素と、脂溶性成分を含有すＲ物質とを有する
複合体からなる近赤外線蛍光トレーサーを提供するもの
である。More specifically, the present invention provides a near-infrared fluorescent tracer composed of a complex having at least a near-infrared fluorescent dye and an R substance containing a fat-soluble component.
【００１１】また、本発明は、少なくとも近赤外線蛍光
色素と、脂溶性成分を含有する物質と、被検出物認識部
からなる近赤外線蛍光トレーサーを提供するものであ
る。The present invention also provides a near-infrared fluorescent tracer comprising at least a near-infrared fluorescent dye, a substance containing a fat-soluble component, and an object recognition unit.
【００１２】さらには、本発明は、赤外線蛍光色素がイ
ンドシアニングリーン系色素であり、前記脂溶性成分を
含有する物質が高密度リポ蛋白質であることを特徴とす
る近赤外線蛍光トレーサーを提供するものである。Further, the present invention provides a near-infrared fluorescent tracer characterized in that the infrared fluorescent dye is an indocyanine green dye and the substance containing the fat-soluble component is a high density lipoprotein. Is.
【００１３】また、本発明は、被検出物認識部が抗体で
あることを特徴とする近赤外線蛍光トレーサーを提供す
るものである。The present invention also provides a near-infrared fluorescent tracer in which the object recognizing part is an antibody.
【００１４】さらには、本発明は、近赤外線蛍光トレー
サーを生体内に導入し、生体を励起光照射し、トレーサ
ーからの近赤外線蛍光を検出することにより体外蛍光イ
メージングする方法を提供するものである。Furthermore, the present invention provides a method for extracorporeal fluorescence imaging by introducing a near-infrared fluorescence tracer into a living body, irradiating the living body with excitation light, and detecting near-infrared fluorescence from the tracer. .
【００１５】以下実施の形態に即して本発明をさらに詳
しく説明する。The present invention will be described in more detail with reference to the following embodiments.
【００１６】[0016]
（近赤外線トレーサー）本発明に係る近赤外線トレーサ
ーは、近赤外領域に蛍光波長を有する色素を含むもので
あり、該蛍光を検出することにより追跡可能とするもの
である。ここで好ましい近赤外領域は、７００ｎｍ、よ
り好ましくは８００ｎｍ以上の範囲であり、また上限は
特に限定されないが、実際の有機系色素においては１２
００ｎｍ〜１６００ｎｍ程度の範囲である。該色素自体
は、少なくとも被検出物が存在する媒体中で蛍光性を有
するものである必要があるが、以下に説明するように必
ずしも水溶液中では蛍光性である必要はない。(Near-Infrared Tracer) The near-infrared tracer according to the present invention contains a dye having a fluorescence wavelength in the near-infrared region and can be traced by detecting the fluorescence. The preferable near-infrared region is 700 nm, more preferably 800 nm or more, and the upper limit is not particularly limited, but it is 12 in the actual organic dye.
The range is about 00 nm to 1600 nm. The dye itself needs to be fluorescent at least in the medium in which the substance to be detected is present, but as described below, it does not necessarily have to be fluorescent in an aqueous solution.
【００１７】また、本発明に係るトレーサーを生物体内
で使用する際には特に必要な特性として水溶性であるこ
と（生体内液体媒体に溶けること）と、該生体に対して
毒性がないことが望ましい。上記の２つの特性を兼備す
る色素であれば本発明においては特に限定されることは
ないが、本発明においては、例えばインドシアニングリ
ーン系の色素が好ましく使用可能である。実際インドシ
アニングリーン系の色素は水溶性であり、肝循環機能検
査用薬として使用されるものであり毒性の点では問題は
ない。Further, when the tracer according to the present invention is used in a living body, it is particularly required that the tracer is water-soluble (dissolves in a liquid medium in a living body) and has no toxicity to the living body. desirable. The present invention is not particularly limited as long as it is a dye having both of the above two characteristics, but in the present invention, for example, an indocyanine green dye can be preferably used. In fact, the indocyanine green dye is water-soluble, is used as a drug for hepatic circulation function test, and has no problem in terms of toxicity.
【００１８】さらに、本発明に係る近赤外線トレーサー
は、好ましくは該色素が他の生体成分に結合した複合体
である。該色素が結合し得る他の生体成分としては、特
に限定はないが、本発明に係るトレーサーの使用目的に
より種々の生体成分を選択可能である。例えば、(1)上
記色素が生体内液体媒体（例えば血液、脊髄液等）に不
溶性である場合に、可溶化するために種々の生体成分と
複合体を形成させることも可能であるし、(2)逆に、上
記色素が生体内液体媒体（例えば血液、脊髄液等）には
可溶性であるにもかかわらず、水溶性の生体内液体媒体
中では、十分蛍光性でなく、むしろ非水溶媒中で蛍光性
となる場合に、種々の生体成分と複合体を形成させるこ
とで蛍光性とすることも可能であるし、(3)さらに、以
下で説明するように本発明に係るトレーサーに被検出物
を特異的に認識する部を導入するために適当な生体成分
と複合体を形成することも可能である。Furthermore, the near-infrared tracer according to the present invention is preferably a complex in which the dye is bound to other biological components. The other biological component to which the dye can bind is not particularly limited, but various biological components can be selected depending on the purpose of use of the tracer according to the present invention. For example, (1) when the dye is insoluble in an in-vivo liquid medium (for example, blood, spinal fluid, etc.), it is possible to form a complex with various biological components for solubilization, 2) On the contrary, although the above dye is soluble in the in-vivo liquid medium (for example, blood, spinal fluid, etc.), it is not sufficiently fluorescent in the water-soluble in-vivo liquid medium, and is rather a non-aqueous solvent. When it becomes fluorescent in, it is also possible to make it fluorescent by forming a complex with various biological components, and (3) further, as described below, the tracer according to the present invention It is also possible to form a complex with an appropriate biological component in order to introduce a part that specifically recognizes the detected substance.
【００１９】実際、上記のインドシアニン系色素は、毒
性の点ではまったく問題ではないが、水溶性溶媒中では
実質的に非蛍光性である。従って、本発明の実施例で示
されるように、インドシアニン色素を脂溶性成分を有す
る生体成分である高密度リポ蛋白質と複合体を形成させ
ることにより、インドシアニン色素を含みかつインドシ
アニン色素を蛍光性とすることができる。In fact, the above-mentioned indocyanine dye does not pose any problem in terms of toxicity, but it is substantially non-fluorescent in a water-soluble solvent. Therefore, as shown in the examples of the present invention, by forming a complex of the indocyanine dye with a high-density lipoprotein which is a biological component having a fat-soluble component, the indocyanine dye is contained and the indocyanine dye is fluorescent. Can be sex.
【００２０】さらに、好ましくは本発明に係る近赤外線
トレーサーは、上記色素に他の生体成分を複合体化した
ものにさらに被検出物を特異的に認識する部を有するも
のである。上記認識部は、被検出物を特異的に認識すれ
ばよく、特に限定されることはない。例えばよく知られ
ている、蛋白質−蛋白質の相互作用に基づくもの、例え
ば抗原抗体結合、レセプターリガンド結合等に基づくも
のが可能である。さらには、被検出物としては、特に限
定されないが、種々の生体内の細胞（例えばガン細胞）
が可能である。上記の認識部を設ける方法は、特に限定
されないが、例えば通常の蛋白質の化学修飾反応で用い
られる結合形成反応が好ましく使用可能である。上記説
明した場合、蛍光色素を含み、かつ被検出物を特異的に
認識する認識部を有するトレーサーが構成されることと
なる。Further, preferably, the near-infrared tracer according to the present invention is a complex of the above dye with other biological components, and further has a portion for specifically recognizing an object to be detected. The recognition unit is not particularly limited as long as it specifically recognizes the object to be detected. For example, a well-known one based on protein-protein interaction, for example, one based on antigen-antibody binding, receptor ligand binding and the like can be used. Furthermore, the substance to be detected is not particularly limited, but various in vivo cells (for example, cancer cells)
Is possible. The method of providing the above-mentioned recognition unit is not particularly limited, but for example, a bond forming reaction used in a general chemical modification reaction of a protein can be preferably used. In the case described above, a tracer that includes a fluorescent dye and that has a recognition unit that specifically recognizes an object to be detected is configured.
【００２１】（近赤外線トレーサーを用いたイメージン
グ）本発明に係る近赤外線トレーサーは、生体内で生体
内液体媒体中で可溶性であり、かつ近赤外線領域で蛍光
性を有するものである。従って、該トレーサーを生体内
に導入し、該トレーサーが、拡散または体液の流動等に
より生体内を移動し、その位置及び濃度変化を生体外か
ら該トレーサーに基づく蛍光を観察することでリアルタ
イムにイメージングすることが可能となる。(Imaging Using Near-Infrared Tracer) The near-infrared tracer according to the present invention is soluble in the in-vivo liquid medium in the living body and has fluorescence in the near-infrared region. Therefore, the tracer is introduced into the living body, the tracer moves in the living body due to diffusion or flow of body fluid, etc., and its position and concentration change are imaged in real time by observing fluorescence based on the tracer from outside the living body. It becomes possible to do.
【００２２】例えば、インドシアニングリーン−高密度
リポ蛋白質（ＩＣＧ−ＨＤＬ）複合体に、抗腫瘍抗体を
化学的に結合させることで、生体内での外腫瘍の位置及
び大きさをリアルタイムで体外計測可能となる。この際
イメージング装置が小型でリアルタイム計測できるの
で、該腫瘍の切除手術中にも用いることが出来るもので
ある。この際腫瘍組織と正常組織の弁別がその場で出来
るので、正常組織を無駄に切除したり腫瘍組織を切除し
残す事がなくなることとなる。For example, by chemically binding an antitumor antibody to an indocyanine green-high density lipoprotein (ICG-HDL) complex, the position and size of an external tumor in vivo are measured in real time in vitro. It will be possible. At this time, since the imaging device is small and can measure in real time, it can be used during excision operation of the tumor. At this time, since the tumor tissue and the normal tissue can be discriminated on the spot, the normal tissue is not wasted or the tumor tissue is not excised and left.
【００２３】また他の表面抗原（組織表面に出たリセプ
ター蛋白やウイルスの外皮蛋白）に対する抗体を標識す
ることにより、腫瘍に限らず任意の抗原が生体内のどの
部分に存在するのか、また、ウイルスに感染した組織は
どれかを簡便かつ特異的に認識することが可能であり、
種々の疾患への診断試薬及び診断方法へ使用可能とな
る。By labeling an antibody against another surface antigen (receptor protein or viral coat protein on the surface of a tissue), it is possible to determine in which part of the body any antigen is present, not limited to the tumor. It is possible to easily and specifically recognize which tissue is infected with the virus,
It can be used as a diagnostic reagent and a diagnostic method for various diseases.
【００２４】例えば、神経軸策流の画像診断として、上
記ＩＣＧ−ＨＤＬ単体を神経筋接合部近傍に投与すれ
ば、神経細胞に取り込まれ、軸策流に乗り、得られる蛍
光を体外計測することで軸策流の測定が観察可能であ
る。For example, as an image diagnosis of nerve axon flow, if the above ICG-HDL alone is administered near the neuromuscular junction, it is taken up by nerve cells, rides on the axon flow, and the obtained fluorescence is measured in vitro. At Axon flow measurements can be observed.
【００２５】本発明に係る上記トレーサーを使用し、該
トレーサーからの蛍光を体外計測するための装置につい
ても特に限定はないが、通常の励起光源と、必要ならば
励起光源用フィルターにより最適な励起光を試料の生体
の外部へ照射し、該励起光により生じる該色素からの蛍
光を蛍光検出器で検出する。この際必要ならば、該色素
からの蛍光のみを選択するためにフィルターを使用する
ことも可能である。さらに、得られた蛍光情報をデータ
ー処理することによりイメージングするものが好まし
い。この際上記データー処理装置につても特に限定され
ることはないが、例えば「ＡＲＧＵＳ２０（浜松ホトニ
クス株式会社製）」が使用可能である。The device for measuring the fluorescence from the tracer in vitro using the above tracer according to the present invention is not particularly limited, but it is possible to optimize the excitation by using an ordinary excitation light source and, if necessary, an excitation light source filter. Light is irradiated to the outside of the living body of the sample, and the fluorescence from the dye generated by the excitation light is detected by the fluorescence detector. At this time, if necessary, a filter can be used to select only the fluorescence from the dye. Further, it is preferable to image the obtained fluorescence information by data processing. At this time, the data processing device is not particularly limited, but, for example, "ARGUS20 (manufactured by Hamamatsu Photonics KK)" can be used.
【００２６】さらには、上記説明したイメージングによ
り、本発明に係るトレーサー、例えばＩＣＧ−ＨＤＬに
抗腫瘍抗体を化学的に結合させることで、腫瘍の位置・
大きさを体外計測できることとなる。この手法を例えば
手術中に行うと、腫瘍組織と正常組織の正確な区別によ
り、正常組織を無駄に切除したり腫瘍組織を切除し残す
のを防ぐための装置の開発に利用され得ることとなる。
この際、ＩＣＧ−ＨＤＬへ抗体を結合させるには、すで
に説明したように例えば、ＨＤＬ部分と抗体を結合（蛋
白質間の架橋反応、通常アミノ基間をグルタルアルデヒ
ドで架橋する等）させる方法、または、ＩＣＧ部分を抗
体のアミノ基に架橋する方法等が可能である。Furthermore, by using the above-described imaging, the tracer according to the present invention, for example, ICG-HDL, is chemically bound to an antitumor antibody to determine the location of the tumor.
The size can be measured outside the body. If this technique is performed, for example, during surgery, the accurate distinction between tumor tissue and normal tissue can be used to develop a device for preventing wasteful removal of normal tissue or removal of tumor tissue. .
At this time, in order to bind the antibody to ICG-HDL, as described above, for example, a method of binding the HDL part and the antibody (cross-linking reaction between proteins, usually cross-linking amino groups with glutaraldehyde, etc.), or , ICG portion can be cross-linked to the amino group of the antibody.
【００２７】（実施例）以下のように、近赤外領域蛍光
色素インドシアニングリーン（ＩＣＧ）とヒト高密度リ
ポプロテイン（ＨＤＬ）との複合体（ＩＣＧ−ＨＤＬ）
を調整したものを使用した。ここで使用したＨＤＬは脂
質と蛋白質が結合した血中蛋白成分である。ＩＣＧは上
で説明したように該ＨＤＬの脂質部分に溶解して、その
結果蛍光性となるものである。得られる複合体は水に可
溶であり、従ってＩＣＧ−ＨＤＬは生体内の種々の部分
にも投与可能であり、かつその近赤外蛍光を体外から観
測するものである。(Example) As described below, a complex (ICG-HDL) of near-infrared region fluorescent dye indocyanine green (ICG) and human high density lipoprotein (HDL).
The adjusted one was used. The HDL used here is a blood protein component in which a lipid and a protein are bound. The ICG is dissolved in the lipid portion of the HDL, as described above, resulting in fluorescence. The resulting complex is soluble in water, so that ICG-HDL can be administered to various parts of the body and its near-infrared fluorescence can be observed from outside the body.
【００２８】ＩＣＧは実際に臨床検査で人体に投与され
ているものであり、またＨＤＬも元来生体成分であるの
で、この複合体を外部から人体に投与しても毒性は少な
い。ICG is actually administered to the human body in clinical tests, and since HDL is also a biological component by nature, external toxicity of this complex to the human body is low in toxicity.
【００２９】(1) ＩＣＧ（ジアグノグリーン、第一製
薬）２０．５ｍｇを蒸留水４ｍｌに溶解し、約５．１ｍ
ｇ／ｍｌ（＝５．５４ｍＭ）水溶液を調整した。(1) Dissolve 20.5 mg of ICG (Diagnogreen, Daiichi Pharmaceutical Co., Ltd.) in 4 ml of distilled water to give about 5.1 m
A g / ml (= 5.54 mM) aqueous solution was prepared.
【００３０】ヒト高密度リポ蛋白溶液（ＨＤＬ，Ｋａｐ
ｐｅｌ社製、２０ｍｇ／ｍｌ）２５０μｌに、ＩＣＧ水
溶液２．５μｌを加え攪拌し、色素ー蛋白複合体（ＩＣ
Ｇ−ＨＤＬ）を調整した。この複合体溶液中のＩＣＧ濃
度は約５５．４μＭである。Human high density lipoprotein solution (HDL, Kap
2.5 μl of ICG aqueous solution was added to 250 μl of 20 mg / ml manufactured by Pel, and stirred to give a dye-protein complex (IC
G-HDL) was adjusted. The ICG concentration in this complex solution is about 55.4 μM.
【００３１】(2) ＩＣＧ−ＨＤＬの光学的特性。(2) Optical characteristics of ICG-HDL.
【００３２】上記のＩＣＧ−ＨＤＬをリン酸緩衝化生理
食塩水（ＰＢＳ）にて５０倍に希釈し、この蛍光スペク
トル（未補正）を測定した。また、比較のために同じ濃
度の有機溶媒（ＤＭＳＯ）溶液のスペクトルも測定し
た。結果を図１に示す（なお、未補正のスペクトルであ
り、蛍光極大値は文献値(A. Schneider, A. Kaboth, L.
Neuhauser : Detection of subretinal neovascular me
mbranes with indocyanine green and an infrared sca
nning laser ophthalmoscope, American J. ofOphthalm
ol., 113-1, 45/51 (1992)とは一致しない)。The above ICG-HDL was diluted 50 times with phosphate buffered saline (PBS), and its fluorescence spectrum (uncorrected) was measured. For comparison, a spectrum of an organic solvent (DMSO) solution having the same concentration was also measured. The results are shown in Fig. 1 (note that the spectrum is uncorrected, and the fluorescence maximum value is the reference value (A. Schneider, A. Kaboth, L.
Neuhauser: Detection of subretinal neovascular me
mbranes with indocyanine green and an infrared sca
nning laser ophthalmoscope, American J. of Ophthalm
ol., 113-1, 45/51 (1992)).
【００３３】この結果から、ＩＣＧ−ＨＤＬ複合体はＤ
ＭＳＯ溶液と同様の蛍光スペクトルを示すことが明らか
である。すなわち、ＤＭＳＯ溶液に対して、ＩＣＧ−Ｈ
ＤＬは５８．３％の蛍光強度（波長８３５ｎｍ）を示
す。From this result, the ICG-HDL complex was
It is clear that it shows a fluorescence spectrum similar to that of the MSO solution. That is, for DMSO solution, ICG-H
DL shows a fluorescence intensity of 58.3% (wavelength 835 nm).
【００３４】(3) ＩＣＧ−ＨＤＬを用いた近赤外線蛍
光イメージング。(3) Near infrared fluorescence imaging using ICG-HDL.
【００３５】上記得られた、ＩＣＧ−ＨＤＬを実際に生
きた実験動物に投与し、ＩＣＧの近赤外蛍光を画像化し
て、ＩＣＧ−ＨＤＬが体内に分布していく様子を体外計
測した。図２には本実施例で使用した測定系の概略を示
す。すなわち、実験動物３にＩＣＧ−ＨＤＬトレーサー
４を導入した後、１５０Ｗのハロゲンランプにバントバ
スフィルター（中心波長７２０ｎｍ）を装着して励起光
源１とし、この光を光ファイバー２を介して実験動物３
に照射する。発生するＩＣＧ−ＨＤＬの近赤外蛍光の検
出にはＴＶレンズ（ＦＵＪＩＮＯＮ ＣＦ８Ａ１：１．
８／８）を装着したＣＣＤカメラ（Ｃ２４００−７５ｉ
浜松ホトニクス（株）製）６を用いた。ただし、ＣＣ
Ｄカメラの赤外カットフィルターは除去し、ＴＶレンズ
にシャープカットフィルター（透過波長８４０ｎｍ以
上）５をセットする。ＣＣＤカメラ６の信号は画像処理
装置７（ＡＲＧＵＳ２０（浜松ホトニクス（株）製））
にて取り込む。The above-obtained ICG-HDL was administered to a live experimental animal, the near-infrared fluorescence of ICG was imaged, and the distribution of ICG-HDL in the body was measured in vitro. FIG. 2 shows an outline of the measurement system used in this example. That is, after introducing the ICG-HDL tracer 4 into the experimental animal 3, a Bunt bass filter (center wavelength 720 nm) is attached to a 150 W halogen lamp to make the excitation light source 1, and this light is transmitted through the optical fiber 2 to the experimental animal 3
Irradiation. A TV lens (FUJINON CF8A1: 1.
CCD camera (C2400-75i) equipped with 8/8
Hamamatsu Photonics KK 6 was used. However, CC
Remove the infrared cut filter of the D camera and set the sharp cut filter (transmission wavelength of 840 nm or more) 5 on the TV lens. The signal from the CCD camera 6 is an image processing device 7 (ARGUS20 (manufactured by Hamamatsu Photonics KK)).
Take in.
【００３６】すなわち、生後３日のウイスター系ラット
（オス）の右脳にＩＣＧ−ＨＤＬ溶液２５μｌを注射器
にて注入した。図３にその反射光像（シャープカットフ
ィルターなし）と近赤外蛍光像（シャープカットフィル
ター装着）を示す。That is, 25 μl of the ICG-HDL solution was injected by a syringe into the right brain of a 3 day old Wistar rat (male). FIG. 3 shows the reflected light image (without the sharp cut filter) and the near-infrared fluorescent image (with the sharp cut filter attached).
【００３７】図３は投与直後の頭部の映像である（蛍光
像におけるＣＣＤカメラの露光時間は１秒間）。投与部
位を中心に前頭部にＩＣＧ−ＨＤＬが分布しているのが
分かる。図４は投与後１時間の頭部の映像である（露光
１秒間）。蛍光像よりＩＣＧ−ＨＤＬの分布が後頭部に
移ってきているのが分かる。また図５は投与後８時間の
体全体の映像である（右が頭部、左が尾部。露光８秒
間）。脊髄の終端にＩＣＧ−ＨＤＬが移動してきたのが
分かる。さらに、図６には、以上の時間変化の結果を、
得られた蛍光強度と時間との関係を明らかにするために
模式的に示したものである。FIG. 3 is an image of the head immediately after administration (exposure time of the CCD camera in the fluorescent image is 1 second). It can be seen that ICG-HDL is distributed in the frontal region centering on the administration site. FIG. 4 is an image of the head 1 hour after the administration (exposure 1 second). From the fluorescence image, it can be seen that the distribution of ICG-HDL has moved to the occipital region. Further, FIG. 5 is an image of the whole body 8 hours after administration (the head on the right, the tail on the left. Exposure for 8 seconds). It can be seen that ICG-HDL has moved to the end of the spinal cord. Further, FIG. 6 shows the result of the above time change,
It is schematically shown to clarify the relationship between the obtained fluorescence intensity and time.
【００３８】この結果は、ＩＣＧ−ＨＤＬが脳から脊髄
の中へと、体表より深い部分を移動していく様子が生き
た実験動物で経時的に観察できることを明確に示してい
る。これはまた、厚みを持った生体試料の観察にＩＣＧ
−ＨＤＬをトレーサーとして使用可能であることを示し
ている。The results clearly show that ICG-HDL migrating from the brain into the spinal cord in a portion deeper than the body surface can be observed with time in a live experimental animal. This is also an ICG for observing thick biological samples.
-Demonstrating that HDL can be used as a tracer.
【００３９】[0039]
【発明の効果】本発明に係るトレーサーの構成、すなわ
ち、近赤外領域蛍光色素と、適当な生体物質との複合体
は、生体内体液中で可溶であり、さらに、水溶液では蛍
光色素としては使用不可能である毒性の低い色素を水溶
液でも蛍光性とするものである。従って、本発明に係る
トレーサーを、蛍光検出装置（励起光源、ＣＣＤカメラ
等の検出系、および画像処理装置）とともに用いること
により生体外で計測してイメージングすることが可能と
なる。The structure of the tracer according to the present invention, that is, the complex of the near-infrared region fluorescent dye and a suitable biological substance is soluble in the body fluid in the living body, and further becomes a fluorescent dye in an aqueous solution. Is a dye that renders an unusable dye of low toxicity even in an aqueous solution. Therefore, by using the tracer according to the present invention together with the fluorescence detection device (excitation light source, detection system such as CCD camera, and image processing device), it becomes possible to measure and image in vitro.
【００４０】すなわち、Ｘ線源・レ−ザ−光源・断層撮
影用検知器・高速コンピューター等は必要なく、同等の
イメージングが可能となる。さらに、簡便・安価なため
に、リアルタイムイメージング（例えば手術中）の応用
も可能とする。That is, an X-ray source, a laser light source, a detector for tomography, a high-speed computer, etc. are not required, and equivalent imaging is possible. Furthermore, because it is simple and inexpensive, it can be applied to real-time imaging (for example, during surgery).
【００４１】また、ＩＣＧ単体を用いた血管造影では適
応部位が限られたが、ＩＣＧ−ＨＤＬを用いればそうし
た制限はない。Also, in the angiography using the ICG alone, the adaptation site was limited, but there is no such limitation if the ICG-HDL is used.
【図１】インドシアニングリーン色素のＤＭＳＯ中での
蛍光スペクトルと、本発明に係るインドシアニン−高密
度リポ蛋白質複合体の水溶液中での蛍光スペクトルを示
す図である。FIG. 1 is a diagram showing a fluorescence spectrum of indocyanine green dye in DMSO and a fluorescence spectrum of an indocyanine-high density lipoprotein complex according to the present invention in an aqueous solution.
【図２】本発明に係るインドシアニン−高密度リポ蛋白
質複合体をトレーサーとして用いた、イメージングのた
めの測定系の概略を示す図である。FIG. 2 is a diagram showing the outline of a measurement system for imaging using the indocyanine-high density lipoprotein complex according to the present invention as a tracer.
【図３】ＩＣＧ−ＨＤＬを投与したラットの投与直後の
反射光像（上）と近赤外蛍光像（下）を示す写真であ
る。FIG. 3 is a photograph showing a reflected light image (upper) and a near-infrared fluorescence image (lower) immediately after administration of a rat administered with ICG-HDL.
【図４】ＩＣＧ−ＨＤＬを投与したラットの投与後１時
間の反射光像（上）と近赤外蛍光像（下）を示す写真で
ある。FIG. 4 is a photograph showing a reflected light image (top) and a near-infrared fluorescence image (bottom) 1 hour after the administration of ICG-HDL-administered rats.
【図５】ＩＣＧ−ＨＤＬを投与したラットの投与後８時
間の反射光像（上）と近赤外蛍光像（下）を示す写真で
ある。FIG. 5 is a photograph showing a reflected light image (top) and a near-infrared fluorescence image (bottom) 8 hours after the administration of ICG-HDL-administered rats.
【図６】ＩＣＧ−ＨＤＬを投与したラットの投与後の時
間変化の結果を、得られた蛍光強度と時間との関係を模
式的に示した図である。FIG. 6 is a diagram schematically showing the relationship between the obtained fluorescence intensity and time, which is the result of time change after administration of ICG-HDL-administered rats.
１…励起光源、２… 光ファイバー、３…試料（ラット
新生児）、４…ＩＣＧ−ＨＤＬトレーサー、５…シャー
プカットフィルター（８４０ｎｍ）、６… 検出機（カ
メラ）、７…画像処理装置、８…蛍光1 ... Excitation light source, 2 ... Optical fiber, 3 ... Sample (rat neonate), 4 ... ICG-HDL tracer, 5 ... Sharp cut filter (840 nm), 6 ... Detector (camera), 7 ... Image processing device, 8 ... Fluorescence
─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成８年８月１５日[Submission date] August 15, 1996
【手続補正１】[Procedure amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】図３[Correction target item name] Figure 3
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図３】ＩＣＧ−ＨＤＬを投与したラットの投与直後の
反射光像（上）と近赤外蛍光像（下）を示す顕微鏡写真
である。FIG. 3 is a micrograph showing a reflected light image (upper) and a near-infrared fluorescence image (lower) immediately after administration of a rat administered with ICG-HDL.
【手続補正２】[Procedure amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】図４[Correction target item name] Fig. 4
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図４】ＩＣＧ−ＨＤＬを投与したラットの投与後１時
間の反射光像（上）と近赤外蛍光像（下）を示す顕微鏡
写真である。FIG. 4 is a micrograph showing a reflected light image (top) and a near-infrared fluorescence image (bottom) of an ICG-HDL-administered rat 1 hour after administration.
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】図５[Correction target item name] Fig. 5
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図５】ＩＣＧ−ＨＤＬを投与したラットの投与後８時
間の反射光像（上）と近赤外蛍光像（下）を示す顕微鏡
写真である。 ─────────────────────────────────────────────────────
FIG. 5 is a micrograph showing a reflected light image (top) and a near-infrared fluorescence image (bottom) 8 hours after the administration of ICG-HDL-administered rats. ─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成８年９月６日[Submission date] September 6, 1996
【手続補正１】[Procedure amendment 1]
【補正対象書類名】図面[Document name to be amended] Drawing
【補正対象項目名】図３[Correction target item name] Figure 3
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図３】 [Figure 3]
【手続補正２】[Procedure amendment 2]
【補正対象書類名】図面[Document name to be amended] Drawing
【補正対象項目名】図４[Correction target item name] Fig. 4
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図４】 FIG. 4
【手続補正３】[Procedure 3]
【補正対象書類名】図面[Document name to be amended] Drawing
【補正対象項目名】図５[Correction target item name] Fig. 5
【補正方法】変更[Correction method] Change
【補正内容】[Correction contents]
【図５】 [Figure 5]
Claims (5)
成分を含有する物質とを有する複合体からなる近赤外線
蛍光トレーサー。1. A near-infrared fluorescent tracer comprising a complex having at least a near-infrared fluorescent dye and a substance containing a fat-soluble component.
成分を含有する物質と、被検出物認識部からなる近赤外
線蛍光トレーサー。2. A near-infrared fluorescent tracer comprising at least a near-infrared fluorescent dye, a substance containing a fat-soluble component, and an object recognition unit.
グリーン系色素であり、前記脂溶性成分を含有する物質
が高密度リポ蛋白質であることを特徴とする請求項１ま
たは２に記載の近赤外線蛍光トレーサー。3. The near-infrared fluorescent dye according to claim 1, wherein the near-infrared fluorescent dye is an indocyanine green dye, and the substance containing the fat-soluble component is a high-density lipoprotein. tracer.
特徴とする請求項２または３に記載の近赤外線蛍光トレ
ーサー。4. The near-infrared fluorescent tracer according to claim 2 or 3, wherein the detected substance recognition unit is an antibody.
線蛍光トレーサーを生体内に導入し、前記生体を励起光
照射し、前記トレーサーからの近赤外線蛍光を検出する
ことによる体外蛍光イメージング方法。5. Extracorporeal fluorescence imaging by introducing the near-infrared fluorescence tracer according to claim 1 into a living body, irradiating the living body with excitation light, and detecting near-infrared fluorescence from the tracer. Method.
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| JP2006234637A (en) * | 2005-02-25 | 2006-09-07 | Aquas Corp | Concentration control method of chemical for water treatment, and tracer material for concentration control of chemical for water treatment |
| JP2008513802A (en) * | 2004-09-21 | 2008-05-01 | ケアストリーム ヘルス インク | Apparatus and method for multimode imaging |
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| US8041409B2 (en) | 2005-09-08 | 2011-10-18 | Carestream Health, Inc. | Method and apparatus for multi-modal imaging |
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