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