JP2006522102A - 光診断法および光線力学的療法の両方のためのターゲット剤 - Google Patents
光診断法および光線力学的療法の両方のためのターゲット剤 Download PDFInfo
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Abstract
Description
本出願は、USSN 60/453,618(2003年3月10日出願)の優先権の利益を主張する一部継続出願(これは、本明細書の一部を構成する)である。
本発明は、ターゲティング分子(targeting moiety)、光線力学的療法(photo dynamic therapy)(PDT)分子(1個または2個のいずれか)、および任意のイメージング(imaging)剤(例えば、発色団、造影剤など)を含む、多機能性(通常、二機能性または三機能性)剤を含有する、方法並びに組成物に関する。
過去5年にわたって、癌性腫瘍の早期検出のための新規なイメージングおよび処置の技術の開発における進行中のルネサンスが存在する。過去数十年間にわたる多数の癌研究者の努力にもかかわらず、癌は未だ米国において2番目の主要な死因であり、これを超えるのは心臓疾患のみである。2002年には米国単独で120万以上の新規な癌の症例が診断されるであろう。これらの内の約70%は、現在活発な開発中の様々なインビボイメージング技術によって早期の検出を受け易い固形癌性腫瘍であろう。患者および保険医療のコストの展望から、特に経過観察の確証的な外科的生検(follow-up, confirmatory surgical biopsies)を排除することができるならば、終夜の病院の滞在を必要としない非侵襲性のイメージング技術が非常に所望されている。これらの新規なイメージング技術がまた同じ患者のセッションにおいて非侵襲的な処置方法と組み合わせることができる場合には、完全な外来患者のイメージング/検出/処置のプロトコールを設計することができ、このものは、現在の診断/外科手術/化学療法/電離放射線療法のプロトコール(これは、過去20年間、処置の標準であった)に置き代わり得る。
上記の目的に従って、本発明は、ターゲティング分子および少なくとも光線力学的療法(PDT)分子(2光子PDT分子(2PM)が好ましい)を含有する、二機能性および三機能性剤を提供する。該薬剤は場合によりイメージング剤を含み、光学的なイメージング剤(例えば、発色団(chromophore)または発発色団(fluorophore)が好ましい)が好ましく、1光子発色団が特に好ましい。加えて、該薬剤は場合によるが通常、リンカーを含み、このことにより、該薬剤の成分の共有結合が可能となる。
本発明は、疾患の検出および処置のために、1以上の外来患者セッションにおいて使用することができる単一試薬に腫瘍(または他の疾患)のイメージングおよび処置のいくつかの面を組み合わせる、多機能性化合物に関する。内視鏡の使用は他のタイプの腫瘍(例えば、固形腫瘍を含む)の検出および処置を可能とすると理解するが、通常皮下癌性腫瘍は、以下に記載する通り、2光子薬剤の波長要件に適当な能力のために良好な候補である。
従来のマンモグラフィーと比較して、デジタルマンモグラフィーは、X−線フィルムの代わりにコンピューターコードでX−線データを記録する。デジタルマンモグラムについての方法は通常のマンモグラフィーのものと同じであり、そしてイメージは電子工学的に保存されるので、長い距離の診察が可能である。しかしながら、デジタルマンモグラフィーが従来のマンモグラフィーよりも癌を検出する際により有効であるとの研究は未だ結論を示していないと報告されている(引用文献10(これは、本明細書の一部を構成する)を参照)。
本技術は、通常のマンモグラフィーによって既に知られる疑わしい領域を放射線科医の目に留めさせるための、コンピューターの使用を含む。これは、置換技術ではなく、むしろ増大である。CADは、放射線科医がより密に診察したいことがあり得る乳の領域をマークする。乳のイメージングのためのCAD技術は、1998年にFDAによって承認され、そしてR2社(R2 Technology, Inc.)はImageCheckerと呼ばれる診断システムを市販し、そして世界中で約200ユニットを売った。
磁気共鳴画像法(引用文献10(これは、本明細書の一部を構成する)を参照)は、無線高周波放射をX−線の代わりに使用する点で、化合物の構造を測定するために広範囲に使用されている核磁気画像システムと同じである。該プロセスは、軟組織の詳細な写真を得る際に非常に正確であるが、しかし、長い患者のセッション(1時間まで)(ここでは、患者はそのままでなければならない)を必要とし、そしてある機械は非常に密室恐怖である。MRIは必ずしも癌性および良性の組織を区別することができるとは限らず、そしてそのものは、微小石灰化を検出することができて、多数の偽陽性を減少させ得る。MRI造影剤は、通常のマンモグラフィーから得られるものよりもずっと鮮明であるイメージを与えることができ、そして、MRIシグナルは脂肪沈着物由来のシグナルによっては損なわれない。Siemens社、Marconi社、Philips Medical Systems社およびGE社は全て開発中のシステムを有し、そしてNIHは、乳癌のための診断用ツールとしてMRIを評価する、14の大学および研究センターの総括コンソーシアムである。上記の通り、MRI造影剤(例えば、DOTAおよびDTPAの誘導体)はイメージング剤として使用することができ、またはMRI(造影剤のあるなし)はアジュバントイメージング工程として使用することができる。
超音波画像技術は、組織および内臓の外に音波をはね返らせ(bounce)、そしてソノグラムと呼ばれるエコー写真を与える。超音波を用いて、マンモグラムにおいては見ることが困難な乳内の塊を評価することができ、そして固形腫瘍および体液充填嚢腫(fluid-filled cysts)の間の区別をすることができる。3D超音波技術(引用文献12を参照)は、腫瘍に関係する乳内の異常な血管の活動を検出することができ、そしてこのものは深さが2インチにまでイメージすることができる。超音波は、癌の早期の徴候を一貫して検出することはできない。
PETスキャンは、低用量の放射性トレーサーを患者に注射することによって、組織内での化学的な変化のコンピュータ化されたイメージを作ることができる。該トレーサーを経口摂取後に、該患者を約45分間そのままにしておかなければならず、その後にPETスキャナーを用いて更に45分間イメージをとり、そして放射性核種の位置および濃度を定量化して、高分解能イメージを得る。PETスキャンは、大きくて且つより高悪性度の腫瘍を検出する際には非常に正確であるが、しかし、8mmよりも小さい腫瘍または高悪性ではない腫瘍を検出する際には良好ではない。PETトレーサーを本発明におけるイメージング分子として使用することができ、またはPETスキャンを本発明のイメージングの方法にとっての補助として使用することができる。
EISは、電気が物質を通って移動するスピードを測定する。乳癌組織は、正常な組織よりもずっと低い電気インピーダンスを有する。これらのデバイスは、典型的なマンモグラフィーと組み合わせて使用され、そして該マンモグラフィーによっては検出されない異常な領域を検出することができる。そのものは、乳癌についての独立型(stand-alone)デバイスとしては承認されておらず、また利用されていない。
共に組織の外に波長をはね返すことによるが、音よりもむしろ光を用いることによってイメージを作る点で、OCTは超音波に似ている。そのものは、伝導性媒質(conducting medium)を必要とせず、従って水および空気を通ってイメージングすることができる。該技術は、2次元および3次元の高分解能イメージに翻訳することができる干渉パターンを作るために、2個のNIR光線を使用する。アドバンスド社(Advanced Research Technologies, Inc.)は、臨床治験においてソフトスキャン(SoftScan)(ここでは、光学的なイメージは、典型的なマンモグラフィーおよびバイプシーと比較される)と呼ばれるシステムを有する。ベックマンレーザー学会(Beckman Laser Institute)(カリフォルニア大学アーバイン校(U.Cal.-Irvine))での研究者(B. Tromberg)は、乳圧迫なしで、深さが数センチメートルにまで約30秒で600〜1000nmの完全なスペクトル写真を捕獲することができるレーザーベースの乳組織スキャナーを開発した。該技術は、酸素化および脱酸素化したヘモグロビン、水および脂肪の濃度、並びに全ヘモグロビン含有量を定量化する。該スキャナー(これは、10NIRレーザーおよび乳組織を通じて照射するために広いバンド域の光源から構成される)は、レーザー光源をMHzからGHzに及ぶ周波数で調節し、ある位相速度で組織を通って伝導する拡散光子密度波(diffuse photon density wave)を作ることによって、吸収および散乱の効果を分離する。初期の研究において、該スキャナーは、年齢の差違、組織密度およびホルモンレベルの変化に関係する乳組織における正常な変化を検出することができた。通常のマンモグラフィーおよび生検との比較を、計画する。クレモン大学(Clemson University)の同様な研究者(H. Jiang)は、16〜3mmの光ファイバー束を通る785nmの光を用いて、5mmよりも小さい癌腫を検出することを可能とした(引用文献14(これは、本明細書の一部を構成する)を参照)。ダートマス大学(Dartmouth College)の研究者(T. McBride)は、16〜3mmの光ファイバー束およびTi:サファイアレーザー(600〜1100nmの領域で操作する)を用いて同様な結果を得ている(引用文献15(これは、本明細書の一部を構成する)を参照)。光学的な断層撮影法は、10cmの直径領域内に包埋されたサブセンチメーター対象物を検出しおよび確認することができることを示した。
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Claims (7)
- a)ターゲティング分子;
b)医学的なイメージング剤;および、
c)光線力学的療法(PDT)分子
を含有する三機能性剤。 - 更にリンカー分子を含有する、請求項1記載の三機能性剤。
- 該医学的なイメージング剤は発色団である、請求項1記載の三機能性剤。
- 該PDT分子はポルフィリンである、請求項1記載の三機能性剤。
- 該PDT分子は置換ポルフィリンである、請求項1記載の三機能性剤。
- 該置換PDT分子は2光子吸収PDT剤である、請求項5記載の三機能性剤。
- 請求項1記載の剤を患者に投与し、そして該PDT剤を活性化するのに十分な光を投与することを含む、癌をイメージングしそして処置する方法。
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