医学研究所 学術フロンティアプロジェクト 「癌感受性遺伝子探索、機能解析、標的評価、新規治療開発、 臨床前試験を一環的に研究する拠点推進プロジェクト」 Ｎ.研究プロジェクト 「ナノ物質を基盤とする光・量子技術の極限追求」医療班 空間干渉Ｘ線源の医療応用：がん治療の革新 A Possible Application of Parametric monochromatic X-ray (PXR) Radiation Induced Photodynamic Therapy ( PDT ) 永瀬浩喜1,2、石橋直也2、3、増子亜矢2，4、五十嵐 潤2、高橋 悟3、高橋元一郎4、 石川紘一5 、松本宜明６、阿部克己3 、齋藤勉3 、藤原恭子2 、田中俊成７、早川建７ 、 早川 恭史７ 、高橋 由美子７、大月 譲8 、新富孝和１ 、佐藤勇１ 1日本大学大学院総合科学研究科生命科学、２医学部癌遺伝学分野、３医学部放射線科、４医学部泌尿器科、 ５医学部薬理学分野、６薬学部臨床薬物動態学ユニット、７日本大学量子科学研究所、８理工学部応用化学 Backgrounds • Parametric monochromatic X-ray (PXR), a new class of coherent X-ray, is a tunable single wavelength and single phase X-ray. • PXR has been developed by using the electron beam from the 125-MeV linac in Laboratory for Electron Beam Research (LEBRA) of Nippon University. • When the PXR are converged, PXR shows a similar characteristic to the Bragg peak of proton beam and heavy ion beam for radiosurgery. • Since PXR is a single wavelength and single phase of soft-to-hard X-ray, it minimizes radiation exposure in the surrounding tissues. 低被爆 • PXRs have a potential to induce photoexcitation of radiosensitive molecules and establish a new PDT antitumor therapy targeting deep internal tumors and metastatic regions in addition to the direct radiation therapy even. 放射線 力学療法 深部臓器への治療 • PDT compounds conjugated with Iodine, which may have an absorbance of around 33KeV coherent X-ray and generate a scintillation light of around 420nm for a photosensitivity material. This may activate and generate singlet oxygen in the target disease tissues. Possible Application of X-ray Induced Photodynamic Therapy ( PDT ) 可視光・赤外光は深部組織に到達できない がん患者の方に PDT薬剤を静脈 注射 約3日後、PDT 薬剤はがんに集 積 光線を腫瘍部位に 充てることでPDT薬 剤を活性化 がん・腫瘍を 特異的に治療 R Photofrin molecular weight 123128～488330 Dissolved in glucose injection and 2mg/kg intravenous. The cancer tissue takes Photofrin four times higher than normal tissue and shows over 48 hours stagnation. In contrast, Photofrin is excreted within 24 hours in all of normal tissue. 48 to 72 hours after injection, the wavelength 630nm laser irradiation can be performed to cancerous regions. 630nm laser reaches the depth of only 5 ~ 10mm in superficial cancer and early cancer (lung cancer, esophageal cancer, gastric cancer, cervical dysplasia and early cancer in use). Induced PDT reaction induces cancer cell death. Our new iodinated photosensitizer Chlorophyll derivatives and iodine conjugate We synthesized iodine (I) conjugated light-sensitive substance Chlorophyll derivatives because iodine as a contrast agent is used in the clinical-ray absorption. I 33.17keV irradiation which is Iodine K-edge absorption can be reached to deep tissues. Iodine conjugated chlorophyll derivatives is currently in clinical trials of phase I/II in the United States for cancer diagnosis. 531 Irradiated iodine compound NaI (Tl) has been known to generate the scintillation light of around 420nm. So, this iodinated photosensitizer may be activated by 33keV coherent X-rays. • がん細胞にだけ取り込まれる物質をさがせ。 • これに致死性の作用をもたせる。 • さらに標識をつければ診断、治療判定まで。 Against Cancer （2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a）HPPH-Cyanine Dye Conjugate: In vivo Fluorescence Imaging H3C H3C C2H5 NH N HPPH N HN H3C C3H mice bearing RIF tumors CH3 O HN C O - CH2CH2CH2 S O Compound 523 O Cyanine dye N CH2 O CH2CH2CH2 S ONa O Relative Fluoresence normalized to blood 2.50 2.00 1.50 1.00 0.50 liv e kid r ne sp y le en tu m or br pa ain nc r in eas te st in m e us c ad le re na l he ar t bl oo d 0.00 7.00 6.00 5.00 4.00 3.00 2.00 1.00 0.00 he ar t bl oo d o O br ai n + CH2 CH3 ne y tu m or sp le en ad re na pa l nc re as m us cle H3C CH CH liv er S kid CH3 CH3 N CH=CH average fluoresence normalized to blood Drug Dose: (i) 0.3 mg/Kg (ii) 3.5 mg/kg 24 h p. i. OC6H13 CH3 Dr. Allan Oseroff， Roswell Park Cancer Institute Against Cancer High 静脈注射後一定期間で腫瘍にのみ集積 Blood Liver Tumor Muscle Biodistribution of HPPH-dye Conjugate Spleen Kidney Adrenal Pancreas Heart Brain Dr. Achilefu WSU, St. Louis Skin A A Blood Blood Muscle Liver Tumor Kidney Spleen Brain Heart pancreas Skin Adrenal B A B Muscle Liver High Tumor Kidney A: 24 h; B: 48 h C: 72 h Dose: 3.5umole/Kg Spleen Brain Heart Low Skin Adrenal CC BCC Low 肺がんのPET CT Scanによる診断 頭頚部癌の遠隔転移 糖代謝が盛んながん細胞を画像化 Positron Emission Tomography （PET） for cancer diagnosis is mainly used to provide a three-dimensional map of flurodeoxyglucose (FDG), which contains a positron emitter whose energy use in the various tissues of the body in order to record the image on a crystal outside the patient. FDG is a modified form of glucose and a simple sugar that is a main energy source. Cancer cells most often use glucose more rapidly than normal cells and can be highlighted as brighter areas on the map. The recorded emissions provide a map of how glucose is used throughout the body. 日本大学電子線利用研究施設のバラメトリックＸ線放射 電子銃 バンチャー 電子線形加速器 集束電磁石 円板装着型加速管 の内部構造 加速管 導波管 方向性結合器 加速管 クライストロン 電子線 集束コイル 集束電磁石 偏向電磁石 反射鏡 クライストロン パラメトリックＸ線発生装置 加速管 ４極電磁石 ミラー 真空箱 単結晶 単結晶 単結晶 電子線 回転 移動 回転 電子線 単結晶 集束磁石 電子線 分析電磁石 偏向電磁石 パラメトリック Ｘ線発生装置 ビーム ダンプ Ｘ線 回転 ０ ビームエキス パンダー ４極磁石 Ｘ線 アンジュ レーター 自由電子レーザー 発生装置 ミラー真空槽 蛇行運動 反射鏡 Ｓ 永久磁石 Ｎ アンジュ レーター レーザー パラメトリックＸ線 電子線 自由電子レーザー 30 m 大実験室 （単位：ｍｍ） １０００ 真空容器 Monte Carlo simulation for 3-D exposure by converged single wave-length coherent X-ray ＥＧＳ５ Ｘｒａｙ （40keV） 生体組織 生体組織 １００ｍｍ 0.１ｍｍφ ５０μ ５０μｍφ がん組織 がん組織 １ｍｍφ １ｍｍφ エネルギーロスｄＥの空間分布 ２０ｍｍφ ２０ｍｍφ ＥＧＳ５ Ｘｒａｙ （40keV） 生体組織の表面 ４０ｋｅＶのＸ線 A model of fine radio-surgery for cancer patient treatment ３次元集束による線量分布 A comparison of energy loss for Proton beam, Carbon Ion beam and coherent X-ray in water Fresnel lens Bragg peaks ＰＨＩＴＳ＋ＥＧＳ５ フレネルレンズ ブラック゛ピーク 癌部 １２Ｃ×1 （220MeV/u） Ｐ×29 （116.5MeV） Ｘｒａｙ×4.9 （40keV） 空間干渉Ｘ線 coherent X-ray Targeting cancer mass in the inner tissue 深部臓器へ有効なX線の線量を到達させることを表層部の被爆を抑えたうえで可能にする K-edge absorption of contrast agent Interactions of incident X-rays with atoms and electrons including electrons in the Kshell skipping with all energy consumption. When incident X-ray energy increases, rapid high dose X-ray absorption is observed. This is K-edge absorption that is unique to various agent. This energy has good contrast to the body (water) in the imaging. Mass attenuation coefficient and photon energy shows a relationship of inverse proportion. Iodine Pyropheophorbide-a derivative conjugate 33.2 KeV PXR O I O Tl 410 nm O O Singlet Oxygen Production Oxidizing critical cellular macromolecules Cell damage/death Absorption of light Photofrin＋Iodine Peak absorption 411nm,661nm Pheophorbide a Peak absorption 415nm,669nm Iodine Pyropheophorbide-a derivative conjugate 33.2 KeV PXR I PAT O O Tl 410 nm O O Singlet Oxygen Production Oxidizing critical cellular macromolecules Cell damage/death Parametric monochromatic X-ray and chlorophyll derivative + iodine ＰＤＴ ク ロ ロ フ ィ ル 誘 導 体 ＋ ヨ ー ド ＰＡＴ Parametric monochromatic X-ray and iodinated chlorophyll derivative combine PDT and PAT. PDT using highly focused and penetrating X-ray. Single wavelength X-ray has no other damage without its wavelength-specific absorption materials in cancer cells. Cell injury by X-ray itself can be expected . Irradiation procedure to cells Radiation shielding by Pb plate over Al plate. K-edge absorption (33.17keV) X-rays Imaging plate 5000cells/well with medium low Kapton film ( prevention of desiccation ) energy high がん細胞のみを標的にした低被爆放射線治療 放射線による力学療法 日本大学電子線利用研究施設（量子化学研究所）のバラメトリックＸ線放射 ＤＥＩ法によるＸ線撮像の配置図 Ｓｉ を僅かに回転 ⇒ ａ，ｂ，ｃ 試料 Ａ 第１単結晶 シールド 電子ビーム 第２単結晶 パラメトリックＸ線 Ｓｉ単結晶 33.2 KeV PXR ＩＰ 単色Ｘ線吸収 コントラスト像 I 放射線増感 Hela cell Hela counts 6633.17keV hours after radiation PXR 1hr33.17Kev 66hrs cultured plate3 for 1 hour cell counts 移動 100 90 80 70 60 50 40 30 20 10 0 がんに集まる 3 radiation shielding 0 concentration of iodinated photosensitizer (μg/ml ) 3 T24 cellT24 counts hours after 33.17Kev radiation PXR72 33.17keV 1hr 72hrs cultured 1.5ml tube for 1 hour O O 25000 O cell counts 20000 O 活性酸素 15000 10000 5000 0 細胞毒性 6 radiation shielding 高い腫瘍集積性 0 6 concentration of iodinated photosensitizer 特許 ポルフィリン誘導体および放射線力学療法におけるその使用 NUBIC案件番号：11483 特願2010-029205 出願日：平成22年2月12日 出願人：日本大学 発明者：永瀬浩喜、高橋元一郎、石橋直也、高橋 悟、増子亜耶、大月 穣、諏訪和也、小林大哉 Acknowledgments Nihon University Kyoto University Satomi Muroi Hiroshi Sugiyama Hiroyuki Nobusue Takamitsu Yano Tadashi Terui Yoshiaki Matsumoto Toshikazu Bando Asako Oguni Shota Uekusa Gentire Biosystems Motonori Kataba Noboru Fukuda Toshio Kojima Makoto Kimura Isao Saito Yuki Yamada Kazunari Yachi Jun Igarashi Roswell Park Takeshi Kusafuka Kaoru Tagata Min Chen Xiaofei Wang Cancer Institute Chisei Ra Yuta Horiuchi Rajeev Mishra Kyoko Fujiwara Fei Song UCSF Cancer Institute William Held Ping Liasng Takayoshi Watanabe Naoya Ishibashi Yoshiko Takagi Jian-Hua Mao Maki Ikeda Shigeki Nakai Allan Balmain Yui Shinojima David Quigley Hiroyuki Kawashima Ryo Hasegawa Cancer Genetics Past members Kenji Naruse Teruyuki Takahashi Tsukasa Suzuki Hiroyuki Asami Eiko Kitamura Aiko Morohashi Chikako Yoshida-Noro Funded by Academic Frontier Project 2006 from MEXT
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