DDS C ,bc ]^ - NEDO · DDS ˘ˇˆ ... DSBL 3.70 ppm DSBL 1.23 ppm BC 100.00 ppm BC 33.33 ppm BC...

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DDSBNCT2 DDS T 50%40 ppmT/B>10 100%
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Transcript of DDS C ,bc ]^ - NEDO · DDS ˘ˇˆ ... DSBL 3.70 ppm DSBL 1.23 ppm BC 100.00 ppm BC 33.33 ppm BC...

  • DDSBNCT

    !"#$%&

    '()*+*+

    2

    ,-.$/0

    12DDS345

    ,678

    9:;[email protected]

    C-,DE5

    FGHIJKLM=

    [email protected]

    FGHMIUB

    V

    -,DQRFGHWXMIUB

    T 67YZ67YZ67

    FGHNOP[\]^

    -,D_`a/03,bc]^C

    deafgRhSTOijkgR

    ilmknobc]^50%pq

    -rsD/0tu4

    vwFGHxy40 ppmpqvT/B>10tu4

    vz{|tXmk}~rsi4

    vwSi4

    v-rsD3_100%

  • 3

    FGHNOPwFGHxyr$_h_`r

    :@>Kh.hhh

    1 tFGHNOPDDStFGH[\]^

    wFGHxy>40 ppm T/B>10 BSH1-1.5hBPA3-4

    23NDDS -,D_`a/[email protected]:;[email protected]

    B-1: FGHIJKLM=B-2:FGHWXDDSD

    ijQR-,D50pqr/0k9:;k67TOth!hij50%pqGr

    C-1:-,DMMB=>BJC-2:9:;67TO

    4

    vvwFGHxy40 ppmpqvw3FGHxy T/B>10

    u4w

    B-1:FGHIJKLM= B-2:FGHWXDDSD

    DDSt,G

    ,67FGHIJKLM=hHVJ-E, HVJ-MIUBhFGHMIUBr,67i

    67wFGHxy40 ppmpqtu4

    GHVJ-E(BSH)FGHxy40 ppmpq, T/B>10tu4FGHMIUBT/B>10tu4 (FGHxy13.4 ppm

    vWX*w!_tu4vFGHMIUB!ij{,hGXftu4

  • 5

    FFGHiFGtIJKLM=FGHNOP

    **tFGHgRD3IJKLM=FGHNOP

    4-Boronophenylalanine Ethylester(BPA-OEt)

    4-Boronobenzylcysteine Ethylester(BBC-OEt)

    NH N

    HNN

    NHHN O O

    HO NO

    O

    NaOONa

    O

    10BHO OH

    10BHOOH

    NH N

    HNN

    NHHN O O

    HO NO

    O

    NaOONa

    O S

    10BHO OH

    S

    10BHOOHEC-028 EC-031

    10B

    COOEt

    HO

    OH

    NH2 10B

    SHO

    OH

    COOEt

    NH2

    . P. 98B-1:FGHIJKLM=

    6

    FFGH.J]FGHi*J=tIJKLM=FGHNOP

    IJKLM={OiJJtgRFGHNOP

    4-Carboran-1-ylmethoxybenzoic acid (CMBA)

    OC

    HC

    OH

    O

    : nBH

    NH N

    HNN

    NN O O

    HO NOHN

    O

    ONa

    O

    ONaOONa

    O

    O

    NaO

    O C

    HC

    : nBH

    EC-032

    . P. 100

  • 7

    67ikFGHIJKLM=EC031, EC032. P. 103

    8

    FGHIJKLM=EC031(bue), EC032(red) 67wxyN

    67wFGHWXg/108 cell)

    >67U251:73.8 ppm

    . P. 104

    . P. 105

  • 9

    FFGHNOPQRHVJ-Envelope (HVJ-E) Vector

    [email protected] !

    B-2:FGHWXDDSD

    "

    #$%&'()**

    Pilot plant !

    + ,+STOijk-.gR

    T 67YZ67YZ67

    -bc/N

    04211i,i23

    -Nucleocapsid, -Polymerase

    HVJ-E (Empty vector)Wild type HVJ HVJ-E (+BSH)HN

    F

    Nucleocapsid(RNA, NP)

    M

    HVJPolymerase

    (P, L)

    45V

    C6/DC7

    SH

    BSHSH

    BSH

    . P.127

    HVJ-E89:;[email protected](DEFGH

    10

    Inactivation BSHLipid mixture

    HVJ-liposome

    Liposome with boronated compound

    HVJ

    SH

    BSH

    HVJ-liposomeI89:9JM4BC(DEKaneda, Y., Dzau, VJ

  • 11

    0

    20

    40

    60

    10 12 14 16

    Added B (ug)Cel

    l B c

    once

    ntra

    tion

    (ug

    /g)

    CT26 LM8

    BSH delivery to cancer cells by HVJ-liposome

    KLrs67i40 ppmtMNkFGHxy[\r!(HVJ-EOPQ

    BSHRSTOU 0.12 0.18 Vg/107cells (4.8-7.2ppm)

    . P. 131

    12

    W#$X''(&()&YX%YZ&

    ,

    +,

    [,

    ),

    \,

    ],,

    ]+,

    ][,

    ]),

    , ^ ], ]^ +, +^ _,

    `Xa'%bY)X''%c$Z&

    '#ded'Y#$X

    Zfgf

    Zfhf

    'ZfYf

    BSHQRHVJ-E80 g 10B/HVJ-E/tumor

    CT26FGHxy

    BSH 80 g 10Biwxy:12-27 ppm

    xy86.4 ppm(75.8 ppm at 1hr, 93.5 ppm at 1.5 hr)

    . P. 133

  • 13

    *c'jX&'(&()&YX%YZ&

    ,f,

    +f,

    [f,

    )f,

    \f,

    ],f,

    ]+f,

    , ^ ], ]^ +, +^ _,

    `Xa'%bY)X''%c$Z&f

    '#ded'k`*)'j*c

    Zfgf

    Zh

    'ZfYf

    CT26iBSHQRHVJ-E!FGHxy

    xy0.5 ppm

    HVJ-E!xy0.5 ppm

    BSH!xy0.6 1.1 ppm2000 g 10B/body lmw24n!xy0.6 ppm

    . P. 133

    14

    >StSiGi*etw!h

    ijoDf_rpqk

    PBSPBS BSHBSH HVJHVJ--EE

    {|

    . P. 161

  • 15

    FFGHMIUB

    double tail

    H. Nakamura, Y. Miyajima, T. Takei, S. Kasaoka, K. Maruyama, Chem. Commun. (Hot paper) 2004, 1910.

    hydrophilic part

    [email protected]

    {E5|rh|f}~{E5|rh|f}~FGHxyFGHxy7.2 mg/kg7.2 mg/kgrhrh14.4mg/kg14.4mg/kgr|~r|~

    NaH

    O OOH

    B-2:FGHWXDDSD

    1FGHMIUB

    16

    n = 16: Stearoyln = 14: Parmitoyln = 12: Myristoyl

    O NH

    O

    OO

    O

    H3C(H2C)n

    O

    H3C(H2C)n

    S

    2-O

    M=BR

    DMCBL (n = 12)DPCBL (n = 14)DSCBL (n = 16)

    OS

    O

    OO

    O

    H3C(H2C)n

    O

    H3C(H2C)n

    2-

    DMBL (n = 12)DPBL (n = 14)DSBL (n = 16)

    O Y

    OS

    2-

    BC (Y = CH2)BCC (Y = NHCOCH2)

    FGHMIUB$

    [email protected]@AB

    BB1212HH1212SH (BSH)SH (BSH)

    SH

    2

    --

    Liposomes consist of phospholipids and cholesterol

    (92006-186907h2006-275367h2006-259290

    . P. 108

  • 17

    % c

    ell g

    rowt

    h

    DM

    BL

    100.

    00 p

    pmD

    MB

    L 33

    .33

    ppm

    DM

    BL

    11.1

    1 pp

    mD

    MB

    L

    3.70

    ppm

    DM

    BL

    1.23

    ppm

    cont

    rol

    DPB

    L10

    0.00

    ppm

    DPB

    L 33

    .33

    ppm

    DPB

    L 11

    .11

    ppm

    DPB

    L 3.

    70 p

    pmD

    PBL

    1.23

    ppm

    DSB

    L

    100.

    00 p

    pmD

    SBL

    33

    .33

    ppm

    DSB

    L

    11.1

    1 pp

    mD

    SBL

    3.

    70 p

    pmD

    SBL

    1.

    23 p

    pm

    DM

    CB

    L 1

    00.0

    0 pp

    mD

    MC

    BL

    33

    .33

    ppm

    DM

    CB

    L

    11.1

    1 pp

    mD

    MC

    BL

    3

    .70

    ppm

    DM

    CB

    L

    1.2

    3 pp

    m

    DPC

    BL

    100

    .00

    ppm

    DPC

    BL

    3

    3.33

    ppm

    DPC

    BL

    1

    1.11

    ppm

    DPC

    BL

    3.70

    ppm

    DPC

    BL

    1.23

    ppm

    DSC

    BL

    100

    .00

    ppm

    DSC

    BL

    3

    3.33

    ppm

    DSC

    BL

    1

    1.11

    ppm

    DSC

    BL

    3.70

    ppm

    DSC

    BL

    1.23

    ppm

    BSH

    100.

    00 p

    pmB

    SH

    33

    .33

    ppm

    BSH

    11.1

    1 pp

    mB

    SH

    3.70

    ppm

    BSH

    1.

    23 p

    pm

    B(O

    H)3

    100.

    00 p

    pmB

    (OH

    )333

    .33

    ppm

    B(O

    H)3

    11.1

    1 pp

    mB

    (OH

    )33.

    70 p

    pmB

    (OH

    )31.

    23 p

    pm

    BC

    100.

    00 p

    pmB

    C33

    .33

    ppm

    BC

    11.1

    1 pp

    mB

    C3.

    70 p

    pmB

    C1.

    23 p

    pm

    667?JWE5

    '"%a`

    "%a`

    . P.110

    18

    * *Zha$)^,

    ]f,

    ],f,

    ],,f,

    ],,,f,

    , + [ ) \ ], ]+ ][ ]) ]\

    c%a'%bY)X'ZXX%cZ%YZ&

    Y#$X'g*#$)'$$_

    50%DPBL (5 mg 10B/kg)MIUBtBNCTE5

    Mice died.

    Tumor disappeared!

    control

    DPBL(50%) Liposomes(5 mg10B/kg)

    BSH (57 mg10B/kg)

    PEGPEG--DPBL(50%)DPBL(50%)FGHMIUBFGHMIUBjxyrjxyr{r}{r}

    G{,CT2667tGiFGHPEGMIUB5 mg 10B/lmh24hr!30$

    V 1.0 x 1012 n/cm2

  • 19

    FGHMIUBGilmkjn!wFGHxy

    !

    "#$%&

    '()*)

    +,-,

    ./01

    2 34!"#$

    . P. 111

    20

    0.600.44

    8.817.60.69

    24h!FGH\

    3hXEh{5h25% or 50% DSBL (10-20 mg B/kg)tin vivomkq3i3

    MIUB~wFGH$

    DSBL 50% 25%w13.4ppm 22.6ppm0.76ppm 37.6ppm

    . P. 111

  • 21

    ,f,

    ],,f,

    +,,f,

    _,,f,

    [,,f,

    ^,,f,

    ),,f,

    ,,f,

    \,,f,

    ,,f,

    , + [ ) \ ], ]+ ][

    '+[`'+,$ded

    (&YX*'`Y

    *'^$ded

    W'+[`'+,$ded

    +^MIUB*FGHMIUBtWijk-E5

    Tumor shrinkage

    PEG

    !;L

    \

    . P. 113

    22

    ,

    ],

    +,

    _,

    [,

    ^,

    ),

    ,

    \,

    ,

    ],,

    , ^ ], ]^ +, +^ _, _^ [,

    +^`Y

    (&YX**(*c

    ^,`Y

    *'

    !rsG

    V ,f*]f[''],]+ &e($+ V ]f*+f]'

    10mg10B/kg >42 days

    0{ 8 days

    5mg10B/kg

    DSBL-FGHMIUBXEhHVJ-FGHMIUB]^E5D

    11FGHMIUBFGHMIUB{E5{E5~~|f}~|f}~

    FGHxyFGHxy7.2 mg/kg7.2 mg/kgrhrh14.4mg/kg14.4mg/kgr|~r|~

    Bioconjugate Chem. 2006, 17, 1310.

    . P. 114

  • 23

    FGHNOPwxy3T/B

    HVJ-E(BSH)i 32mg 10B/kg G{,xy86.4 ppm, xy0.5 ppmG0q,xy135 ppm, xy0.5 ppmwFGHxy40ppmpq, T/B>10tu4BSHG{,iwxy:12-27 ppmhxy0.6-1.1 ppm

    2FGHMIUBG{,Ji20mg 10B/kg 24n!wxy13.4 ppm, T/B=17.6T/B>10tu4

    [email protected]{,Ji >40ppm, T/B>10 u4!1FGHMIUB(Bioconjugate Chem. 17, 1314-20, 2006)7.2mg 10B/kg 24n!wxy23.1 ppm, T/B=2.3BSHQRTf-PEG-liposome (J. Control. Release 98, 195-207, 2004)35 mg 10B/kg 72n!wxy33.1ppm, T/B=6.0BSHQRPEG-liposome (J. Control. Release 98, 197-205, 2004)35 mg 10B/kg 72n!wxy24.3ppm, T/B=2.5

    24

    vvijQR-,Dr50%pq/0kv!hij50%pqGr

    u4w

    C-1:-,DMMB=>BJC-2:9:;67TO

    vtQRmk3QR-rsD,pqMMBi4v9:;[email protected][email protected]!h_ih23rzf}~

    !lIv*[.rhtzkZk~BA3h-rsD39:;67TO,w{,thGi67tmk3],,}h45rk~

    E5vFGHNOPWXPEG-CG-HVJ-Eij}~iz{|tXmkGi4

  • 25

    4$MIUB100 nmXV$34/VIRSI kirrad / kcont

    q4rO/Vwm~

    XChol

    X DLO

    PC XDSPC

    0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

    0

    0.1

    0.2

    0.3

    0.4

    0.5

    0.7

    0.6

    0.8

    0.9

    1

    1

    0.9

    0.8

    0.7

    0.6

    0.5

    0.4

    0.3

    0.2

    0.1

    0

    OO

    OO O

    P OO O-

    N+

    H H

    Dilinoleoyl phosphatidylcholine(DLOPC)

    OO

    OO O

    P OO O-

    N+Distearoyl phosphatidylcholine(DSPC)

    HO

    H

    H

    H

    Cholesterol (Chol)

    3

    MIUB4

    Akamatsu, K., Effect of ionizing radiation on membrane permeability of liposome: the dependency of lipid composition, concentration, and radiation dose/dose-rate, Chem. Phys. Lipids, to be published.

    . P. 116

    C-1: t-,D=>BJMMB

    26

    0

    20

    40

    60

    80

    100

    0 5 10 15 20 25Time for incubation (h)

    Effl

    ux (%

    )

    ijkFGHWMIUB DLOPC: DSPC: BC: Chol = 20: 20: 20: 40 hDLOPC: DSBL: Chol = 20: 20: 60 / M=pH 7.4-,DJ=/0=>BJh~MIUBxy),'$h],xy],,,'hh$~

    [email protected]

    -,D

    10BWX10B 10B

    10B

    10B10B

    10B10B

    10B

    SO

    O

    H

    H

    H

    S

    O

    OOC17H35

    O

    C17H35

    OBC DSBL

    3Chol{O+QWX

    . P. 123

  • 27

    MIUBwi3(%Xjh*%YZ&tQRmk

    10B4He, 7LihMIUBSt~

    carboplatinBSH3Ii/Nmk~ BSHxyr3MIUB4r

    (%Xjh*%YZ&3zkNO4

    B SHH2O2

    2 Na+

    : BH

    2 Na+

    B S BS

    2 Na+

    ~ pH 11

    28

    QRMIUBtOv [email protected] 1.64 x 109 n/cm2/s

    v n 4n

    v xy ~ 10 mM

    v w010B: 226 ppm

    v w0Ptxy 8 ppm

    Pt

    Pt

    Pt

    PtPt

    Pt

    vMIUB4DLOPC: DSPC: Chol = 2: 2: 6

    Carboplatin

    BSSB10BFGHNOP

    /0

    0.9 % NaCl

    h92008-041048/V$MIUBhtMIUBDhiMIUB Akamatsu, K., Development of thermal neutron- sensitive liposome for a novel drug delivery system aiming for radio-chemo- concurrent cancer therapy, Radiat. Phys. Chem., to be published.

    ,

    +,

    [,

    ),

    \,

    ],,

    QRf

    QRf

    QR

    QR

    =;?B>

    _h[n

    /VhMIUBijk-rsD=>BJMMB

    . P. 125

  • 29

    C-29:;67TO

    *

    N.S.

    0

    100

    200

    300

    400

    500

    600

    700

    800

    900

    1000

    0 5 10 15 20 25

    Days after tumor inoculation

    HVJ-E

    AdVSaline

    Suppression of CT26 growth in vivo by HVJ-EKurooka, M, Kaneda, Y: Cancer Research, 2008.

    Tumor-free mice

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100:1 50::1 25:1 12.5:1 6:1 3:1

    ET ratio

    67T 67g

    HVJ-E

    Control

    . P. 162

    2007113;116

    300

    0.1

    0.2

    0.3

    0.4

    0.5

    0.6

    0.7

    0.8

    0.9

    1

    0 5 10 15 20

    Days after inoculation

    HVJ-Eijk.ijlr_

    *

    HVJ-E or saline injection into the right flank tumor

    CT26 inoculationin the right flank

    Day -4 Day 0 Day 4 Day 8

    CT26 inoculationin the left flank

    HVJ-E or saline injection into the right flank tumor

    HVJ-E or saline injection into the right flank tumor

    Monitor tumor formationat the left side

    Rat

    io o

    f tum

    or-f

    ree

    mou

    se G

  • 31

    HVJ-E

    YZ67

    NK

    T 67

    IFN-,-

    NFkB

    IL-6IFN-,-

    Reg. T

    NK67/N _`T 67_

    ,678

    YZ67/N

    CTLg

    HVJ-Eijk-Jr

    IFN-?

    . P.164

    32

    (A) Rantes

    (B) IFN-

    (C) IL-12

    *%'hde$*

    ,+,

    [,),

    \,],,

    ]+,

    * WXZY&',f] Wk\,',f,] Wk\,',f,+ Wk\,',f,^ Wk\,',f]

    *

    *%'hde$*

    *]+

    *],

    ,

    ],

    +,

    _,

    [,

    * WXZY&',f] Wk\,',f,] Wk\,',f,+ Wk\,',f,^ Wk\,',f]

    *

    *]+'hde$*

    %&Y)a

    *],,

    ,

    ],,

    +,,

    _,,

    [,,

    ^,,

    * WXZY&',f] Wk\,',f,^ Wk\,',f] Wk\,',f+ Wk\,',f[

    *

    %&Y)a'hde$*

    HVJ-Eijk!>=h=gQRikDetergentij}_`!

  • 33

    siRNA

    Tf-F

    Wild HVJ

    HN (-)/Tf-F (+)HVJ

    HN mRNA

    HN-mRNAdegradation

    a$tXHNt"#agRHVJ-EJ. Biotechnology 2008, BBRC, 2007, Human Gene Ther. 2007

    Tf-Fstable transformant,,f+,f[

    ,f)

    ,f\

    ]

    ]f+

    ]f[

    ]f)

    &X$%* a(X%$j*) *aZ

    X)*%YZg)'X%YZ

    Hemagglutinating Activity Assay

    HN

    Cont. SiRNA

    F

    HN"#3$%[_

    . P.148

    . P. 145

    (2007185;;1

    34

    HEK293(Low TfR) HeLa (High TfR)

    Tumor-specific infection of HN-depleted targeting HVJ

    HN-depleted HVJ with Tf-F

    HN-depleted HVJ

    Wb* (`Z$)X%

    . P. 149

  • 35

    Tf-F HVJ-E chimera HVJ-E

    ,

    ],

    +,

    _,

    [,

    ^,

    ),

    ,

    \,

    ,

    kZ**c (`Z$)X%

    YY%*'

    &cY

    Q-dotQRTf-FJHVJ-Ea'lmw!48n

    !Tfi(ka$tk

    Tf-F HVJ-EijkQ-dotw$)h}~iPi0*o)i0

    Wild HVJ-E+~iO0

    . P. 150

    36

    CC NNOO

    NHNH22

    NHNH22

    Cationized Gelatin ( CG)HVJ-E

    +

    CG-HVJ-E

    ,=N-=./HVJ-Eijkw0P1u

    ,

    ],,,

    +,,,

    _,,,

    [,,,

    ^,,,

    ),,,

    ,,,

    \,,,

    ,,,

    * *2

    *$h`f

    *#&d

    *Zg)X

    ah*))&

    Tumor nodule

    Liver Spleen

    HVJ-E CG-HVJ-E

    3i{|t4G

    Intraperitonealinjection

    J. Gene Medicine, 7, 888-897, 2005) . P.152

  • 37

    ,^,,,,],,,,,]^,,,,+,,,,,+^,,,,_,,,,,_^,,,,

    *

    *

    X)Z$

    $#&)

    &YZ*'j']

    &YZ*'j'[

    "XY$

    %&&Z&',

    "XY$

    %&&Z&'+^

    #(Zb)X%a)'%(YZgZY

    '

    5

    CG-HVJ-Eijk67TO89ilmk-:;tmk3_krh

    B=D>3s+_f

    38

    567689:;[email protected]

    0102030405060708090

    100

    0 10 20 30 40 50 60 70 80 90 100

    [email protected]/

    [email protected]

    EF GF HF EF GF HF GF HF

    G

    Day

    Surv

    ival

    Rat

    io (%

    )

    PBS BLM CG/BLMHVJ-E/BLM

    CG-HVJ-ECG-HVJ-E/BLM

    CG-HVJ-E/BLM

    BleomycinQRHVJ-E3wijk3S,(Mima, H., et al. and Kaneda, Y.: Mol. Cancer Ther. 2006)

    38

  • 39

    Control Mice Survived MiceMol. Cancer Therapy, 2006)

    IJKCT26LMNOPQ

    4: 0/44: 3/3

    39

    40

    DXR DXR/HVJ-E

    2/6 (33%) 0/10 (0%)Tumor

    Gi

    -rsDCHVJ-Eij!Gi

    %',

    ,[email protected]

    *CsUJA=sUJA=RD

    (Cancer Chemother. Pharmacol., 2008)

    BC,JikE5

    2/2

    0/2

    Tumor

    Naive

    HVJ-E/BLMtreated

    %',

    {,67W+)

    D E

    *vw3w

    {,

    JikE5

    BMC Medicine., 2008)

    . P. 165

  • 41

    PEG{{O,=N-=./HVJ-ECH2NH

    C

    NH

    (CH2)3N:H+Cl-

    CH3

    H3C

    O

    CH3

    ++ ++ ++

    gelatingelatin(IEP=9.0)(IEP=9.0)

    EDCEDC(1(1--ethylethyl--33--(3(3--dimethylaminopropyl)dimethylaminopropyl)--

    carbodiimidecarbodiimide,, hydrochroridehydrochroride))

    EthylenediamineEthylenediamine cationizedcationized gelatingelatin

    CH3CH2NH

    CH

    N

    (CH2)3N:H+Cl-

    CH3

    H3C

    NH2CH2CH2NH2

    NH2

    CO

    OH

    NH2

    C

    O

    NH

    CH2CH2NH2

    37 O C

    pH 5

    HVJ-EPEG

    PEG-CG-HVJ-E

    92007-157701,[email protected](DEFGHhFGHhIJKL

  • 43

    }}

    [email protected]!hWijkE5

    Liver Weight (g)

    0 1 2 3 4

    PEG-CGHVJ-E

    CGHA-HVJ-E

    CG-HVJ-E

    HVJ-E

    BSH

    normal liver

    BNCT(-)

    Control Normal Liver BSH

    HVJ-E CG-HVJ-E PEG-CG-HVJ-E

    10B concentration:BSH; 1,000 gB/ headHVJ-E BSH, Polymer HVJ-E BSH; 13.6 gB, 1,500 HAU/head

    (QR4

    . P. 160

    44

    FFGHNOPgR!}~)th9JKBVs>t0

    Tumor

    NormalLiver

    BSH 750 gB BSH 30 g B PEG-CG-HVJ-E BSH 25 gB

  • 45

    BSHQQRPEG-CG-HVJ-E tBNCT!S,G}~)

    Normal Liver

    Tumor

    zLM=T$UV

    4646

    45i

    [\FGHDDSD

    -rsD=>BJMMB

    u4y

    45W

    XaYZ[\]f+

    45^

    vFGHNOPQRHVJ-E)[email protected]/B>[email protected]=hBSHQRHVJ-liposome,67i67wFGHxy40 [email protected]~

    v-rsDMMB=>[email protected]:;67TOtvBNCT!_v.`.~matzkbcde~v9:;67TO3-rsDG!100%~

    vBSH/[email protected]~vBSH/HVJ-E, FGHMIUBthmaikjrsl3fgk~v,afklmw|MGf+iOXEr3Nk~

    v-rsD=>BJMMBMIUB~q/ViOr/Vyinrk~v9:;67TO~*[email protected]~qij,_wrsO_zh,2oO!ifh7f/ipq~

    Mw09:DMr01FGHMIUB3hv/VMIUBh,[email protected]

    vQRh=RsQR44tsf16thuv11tv&Mw81hM523v15(FGHMIUB3BNCTr3haNHVJ-E, 9:;E5)

  • 47

    DDSDN|

    HVJ-EBTB9wBid0;NOD

    20091 20101 20151 20201

    FGHMIUB

    IMBHVJ-E

    RD RD :L9x

    GLP

    ,Shyz{h

    {,}f+

    D|B

    GLP ijk,

    FGHIJKLM=

    BSH KBxyz{GLP

  • DDSBNCT

    !"#$%&

    '()*+*,

    BNCT

    DDS

  • FFAG

    PET

    P.179

    JCDS

    Dose (Gy)

    CT

    MRI

    PET

    PHITS

    PET

    CT MRI PET

    P.179

  • PET

    Neutronbeam

    CT 1x1x1mm3

    5x5x5mm3

    PETP.180 182

    PHITSP.182

    PHITS (Particle and Heavy Ion Transport code System)

  • MCNP PHIT

    0.0E+00

    5.0E+08

    1.0E+09

    1.5E+09

    2.0E+09

    2.5E+09

    3.0E+09

    3.5E+09

    MCNP-Thermal

    PHITS-Thermal

    0.0E+00

    4.0E+08

    8.0E+08

    1.2E+09

    1.6E+09

    2.0E+09

    MCNP-Epithermal

    PHITS-Epithermal

    0.0E+00

    2.0E+07

    4.0E+07

    6.0E+07

    MCNP-Fast

    PHITS-Fast

    (n/c

    m2

    s)(n

    /cm

    2s)

    (n/c

    m2

    s)

    10keV 20MeV

    0.53eV 10keV

    0.53eV

    (cm)

    (Gy/

    h/pp

    m)

    (Gy/

    h)

    0.53eV

    0

    0.2

    0.4

    0.6

    0.8

    Boron MCNP

    Boron PHITS

    0

    0.3

    0.6

    0.9

    1.2

    1.5

    Hydrogen MCNP

    Hydrogen-PHITS

    (Gy/

    h)

    0

    0.3

    0.6

    0.9

    1.2

    1.5

    1.8

    Nitrogen MCNP

    Nitrogen-PHITS

    (cm)

    P.182 184

    P.184 185

  • 100806040

    20

    10 30 50

    90

    70

    100806040

    20103050

    90

    70

    Dose Volume Histogram

    MCNP

    P.184 185

    PHITS

    FFAG

    FFAG

    1x109

    (MeV)

    Flux

    (n/c

    m2

    s)

    1.0E+06

    1.0E+07

    1.0E+08

    1.0E+09

    1.0E-08 1.0E-06 1.0E-04 1.0E-02 1.0E+00

    Void)

    AlF3 Al

    Bi

    LiF+PE

    Gr.

    10

    P.186 187

  • XZ

    Void

    LiF

    LiFAlF3 Al

    40cm 20cm

    FFAG BNCTP.188 189

    (n/c

    m2

    s)1.0E+05

    1.0E+06

    1.0E+07

    1.0E+08

    1.0E+09

    1.0E-08 1.0E-06 1.0E-04 1.0E-02 1.0E+00

    (MeV)

    11

    JRR-4

    0.0E+00

    5.0E+07

    1.0E+08

    1.5E+08

    2.0E+08

    2.5E+08

    3.0E+08

    0.0 2.0 4.0 6.0 8.0 10.0

    (cm)

    (cm)

    (n/c

    m2

    s)(G

    y-E

    q)

    20mm

    (cm)

    (n/c

    m2

    s)(G

    y-E

    q)

    0.0E+00

    5.0E+07

    1.0E+08

    1.5E+08

    2.0E+08

    2.5E+08

    3.0E+08

    3.5E+08

    0.0 2.0 4.0 6.0 8.0 10.0

    12

    (cm)

    15mm

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

    Tumor Dose RateNormal Tissue Dose RateSkin Dose Rate

    0

    10

    20

    30

    40

    50

    60

    70

    80

    0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

    Tumor Dose RateNormal Tissue Dose RateSkin Dose Rate

    43 37

    P.189 190

    T/N :1040ppm

    T/N :1040ppm

  • 13

    P.191

    ICP-AES PGA

    ICP-AES

    JRR-4 ICP

    ICP-AES PGA

    -25.0

    -20.0

    -15.0

    -10.0

    -5.0

    0.0

    5.0

    10.0

    15.0

    20.0

    25.0

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    PGA

    (%)

    ICP-

    AES

    (ppm

    )

    PGA (ppm)

    BSH BSH+BPA)

    BPA

    ( )

    JRR-4 PGA

    Epi-33 Epi-33Mode

    20W

    100W

    BSH

    &BPA

    12:0010:00

    Epi-8

    200kW

    PGA

    11:50

    BSHICP

    10:50

    ICP

    PGA

    3:50 11:15

    BPA

    11:50

    BSH

    4:50 5:50

    BSH

    23:000:00

    PGAICP

    PGA ICP-AES

    14

    P.193

  • JRR-4

    JRR-4

    15

    P.191 192

    BNCT

    BNCT

    SOF

    SOFBC-490)6LiF

    (1mm )

    16SOF SPND

    SOF

    SPND

    SPND SOF

    P.193 195

  • BNCT SOF

    SOF BNCT

    17

    P.194 196

    SOF

    SOF SPND 2

    JCDS

    Dose (Gy)

    CT

    MRI

    PET

    ROI

    18

    SOF

    ROI

    P.198

  • (1)

    (3)

    19

    2008 2009 2010

    BNCT JRR-4 KUR

    BNCT

    BNCT

    JRR-4

    FFAG

    FFAG-DDS FFAG

    FFAG

    202020

    BNCT

    BNCT BNCT

  • 1-1

    15 10

    NEDO

    ()

    NEDO

  • 1-2

  • 1-3

  • 1-4

    (1) NEDO

    NEDO

    (2)

    (1)

    (2)

    (3)

  • 1-5

    (4)

    (1)

    (2)

    (3)

    (4)

  • 1-6

    (1)

    (2) NEDO NEDO

    (2)

  • 1-7

    (1)(2)

    (1)

    (2)

    (1)

  • 1-8

    (2)

    (3)

    andor

    (4)

    (1)

  • 1-9

    (2)

    (3)

    (4)

    (1)

    (2)

  • 1-10

    (3)

  • 1-11

    (1)

    (2)

    (3)

    (4)

    (1)

  • 1-12

    (2)

    (1)

    (2)

    (3)

  • 1-13

    (4)

    (1)

    (2)

  • 2-1

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