Nanoparticles in cancer medicine a physician’s amos3.aapm.org/abstracts/pdf/127-37397-418554- Nanoparticles in cancer medicine – a physician’s perspective Sunil Krishnan, MD

  • View
    216

  • Download
    3

Embed Size (px)

Text of Nanoparticles in cancer medicine a physician’s amos3.aapm.org/abstracts/pdf/127-37397-418554-...

  • 1

    Nanoparticles in cancer medicine

    a physicians perspective

    Sunil Krishnan, MD

    John E. and Dorothy J. Harris Professor

    Director, Center for Radiation Oncology Research

    MD Anderson Cancer Center

    Disclosure Information

    Sunil Krishnan

    I have the following financial relationships to disclose:

    Grant or research support from:

    NIH, DoD, CPRIT, Alliance for Nanohealth, Shell,

    Hitachi, FUSF, Dunn Foundation, MDACC

    Royalties

    Taylor and Francis (book sales)

    I WILL NOT include discussion of investigational or off-label use of a product in my presentation.

    Physical dose enhancement

    Hainfeld et al. Phys Med Biol 2004; 49: N309-15

  • 2

    The underlying physics

    Ejection of orbital electron & emission of x-ray

    fluorescence photon (or characteristic x-ray)

    4

    K

    L

    M Courtesy: Nivedh Manohar, PhD

    Physical dose enhancement

    Cho et al. Phys Med Biol 2009

    Physical dose enhancement

    Cho et al. Phys Med Biol 2009

  • 3

    Physical dose enhancement

    Cho et al. Phys Med Biol 2009, 54(16):4889-905.

    Physical dose enhancement

    Cho, Krishnan Med Phys 2010

    Physical dose enhancement

  • 4

    Internalization

    14nm

    74nm

    50nm

    Chithrani DB, et al. Rad Res 2010 173(6):719-728. 2010 .

    14nm 74nm

    50nm

    Enhancing physical dose enhancement

    hn

    nanoparticles

    + peptides

    Active targeting

    on the order of 10 m

    e- e-

    e-

    nanoparticles

    hn

    Passive targeting

    Conjugated gold nanorod

  • 5

    Gold nanorod

    Control 30 min 4 hrs 24 hrs

    PE

    G-G

    NR

    C

    22

    5-G

    NR

    Krishnan lab, unpublished data

    Tumor regrowth delay

    0.8

    1.0

    1.2

    1.4

    1.6

    1.8

    2.0

    2.2

    2.4

    2.6

    2.8

    3.0

    3.2

    3.4

    3.6

    3.8

    4.0

    0 5 10 15 20 25 30

    No

    rma

    lize

    d T

    um

    or

    Vo

    lum

    e

    Days after treatment

    Control

    PEG-GNR

    C-GNR

    Cetuximab

    Rad

    Cetuximab + Rad

    PEG-GNR + Rad

    C-GNR + Rad

    Biodistribution

    0

    5

    10

    15

    20

    25

    30

    35

    40

    45

    Brain Heart Lung Liver Spleen Kidney Tumor Blood

    % ID

    PEG-GNR

    C225-GNR

    Cho SH. Phys Med Biol 2005; 50: N163-73

  • 6

    Clonogenic survival

    Dose (Gy)

    0 2 4 6 8

    Su

    rviv

    ing

    Fra

    cti

    on

    0.000

    0.001

    0.010

    0.100

    1.000

    Control

    PEG-GNR

    C225-GNR

    Dose (Gy)

    0 2 4 6 8

    Su

    rviv

    ing

    Fracti

    on

    0.000

    0.001

    0.010

    0.100

    1.000

    Control

    PEG-GNR

    C225-GNR

    DEF 10% DEF 15%

    30 min 24 hrs

    DNA damage

    DNA damage

    0

    10

    20

    30

    40

    50

    60

    70

    0.05 0.5 1 2 4 24

    Av

    era

    ge

    Nu

    mb

    er

    of

    Fo

    ci p

    er

    ce

    ll

    Time after irradiation (hrs)

    No Radiation

    Radiation (4 Gy)

    GNR + Rad (4 Gy)

    C225-GNR + Rad (4 Gy)

    H2AX

    H2AX

    PARP

    C 0 1 4

    R4 + GNR R4 + cGNR

    C 0 1 4 C 0 1 4

    R4

  • 7

    Apoptotic markers

    0

    0.5

    1

    1.5

    Rad pGNRcGNR

    -N

    TP

    ra

    tio

    G H

    1 hr

    Ra

    d

    -20.0 -15.0 -10.0 -5.0 ppm (t1) -20.0 -15.0 -10.0 -5.0 -20.0 -15.0 -10.0 -5.0

    24

    hr

    Contro

    l

    pGNR

    cGNR

    NTP

    NTP

    NTP

    Procaspase 3

    Procaspase 9

    Procaspase 8

    Actin

    pGNR + Rad cGNR + Rad Rad (4 Gy)

    C 0 1 4 24 C 0 1 4 24 C 0 1 4 24 hr post IR

    Caspase mediated apoptotic markers Mitochondrial mediated apoptotic markers E

    Bcl-2

    PUMA

    Bax

    pGNR + Rad cGNR + Rad Rad (4 Gy)

    C 0 1 4 24 C 0 1 4 24 C 0 1 4 24 hr post IR

    Actin

    Total oxidative stress

    0.8

    0.8

    0.9

    0.9

    1.0

    1.0

    1.1

    1.1

    1.2

    1.2

    1.3

    Control Immediate 1 hr 4 hrs

    No

    rma

    lize

    d p

    rote

    in c

    arb

    on

    yl c

    on

    ten

    t

    Time after 4 Gy radiation

    Rad

    GNR

    CGNR

    Protein carbonyl assay

    Tissue effects

    4 hrs 4 days

    Post irradiation time

    Ra

    dia

    tio

    n

    PE

    G-G

    NR

    +

    Ra

    dia

    tio

    n

    C2

    25

    -GN

    R

    +

    Ra

    dia

    tio

    n

  • 8

    Tissue effects

    0

    50

    100

    150

    200

    250

    300

    350

    4 hrs 4 days

    Post irradiation period

    Avera

    ge m

    icro

    vessel d

    en

    sit

    y

    per

    field

    of

    vie

    w w

    ith

    10X

    ob

    jecti

    ve

    Radiation (10 Gy)

    GNR + Rad (10Gy)

    C225-GNR + Rad (10 Gy)

    *

    Intracellular distribution

    Time

    Intracellular distribution

    Wolfe T, et al. Nanomedicine 2015;11:1277-1283

  • 9

    The underlying physics

    Ejection of orbital electron & emission of x-ray

    fluorescence photon (or characteristic x-ray)

    25

    K

    L

    M Courtesy: Nivedh Manohar, PhD

    Summary

    Bhattarai SR, et al. Nanoscale. 2017 Apr 20;9(16):5085-5093.

    Targeted payload delivery feasible with smaller

    nanoparticles bioconjugated to peptides/antibodies

    Tumor accumulation does not increase much, BUT

    distribution is altered at the cellular level

    Both the intracellular localization and the perivascular

    sequestration result in greater radiosensitization at a

    biological level, mediated primarily by: Increased DNA damage and downstream signaling

    Increased oxidative stress

    Increased vascular disruption

    Summary

  • 10

    Another approach

    Thermosensitive liposome

    PEG

    AuNp

    Aqueous core

    Phospholipid

    bilayer

    Hydrophobic region

    12

    0-1

    30

    nm

    26 28 30 32 34 36 38 40 42 44 46 48 50 52

    0

    20

    40

    60

    80

    100

    41.5 o

    C

    TSLAuNps

    NTSLAuNps

    Perc

    en

    t o

    f A

    uN

    ps r

    ele

    ased

    Temperature ( o

    C )

    38.5 oC

    Focused ultrasound

  • 11

    Radiosensitization

    0 3 6 9 12 15 18 21 24 27 300

    50

    100

    150

    200

    250

    300

    350

    400

    Control

    HT

    TSLAuNp

    Rad

    TSLAuNp + Rad

    TSLAuNp + HT+ Rad

    Days

    No

    rmali

    zed

    tu

    mo

    r vo

    lum

    e

    Radiosensitization

    0 3 6 9 12 15 18 21 24 27 300

    50

    100

    150

    200

    250

    300

    350

    400Control

    HT

    TSLAuNp

    TSLAuNp + HT

    Rad

    TSLAuNp + Rad

    TSLAuNp + HT+ Rad

    AuNp+Rad

    NTSLAuNp + Rad

    NTSLAuNp + HT

    NTSLAuNp + HT + Rad

    HT+ Rad

    Days after intravenous injection

    No

    rmalized

    tu

    mo

    r vo

    lum

    e

    Deep penetration of tumors

  • 12

    Summary

    Triggered release from thermosensitive liposomes

    enhances deep penetration of nanoparticles

    Deep penetration improves radiosensitization

    independent of the effect of hyperthermic

    radiosensitization

    In principle, this could be a class solution for a variety

    of tumor types

    Photoacoustic imaging

    (A)

    (B)

    (C)

    (A1)

    (A2)

    (A3)

    (A4)

    Xray fluorescence imaging

    Manohar N, et al. Sci Rep. 2016 Feb 25;6:22079.

  • 13

    0.8

    1.0

    1.2

    1.4

    1.6

    1.8

    2.0

    2.2

    2.4

    2.6

    2.8

    3.0

    3.2

    3.4

    3.6

    3.8

    4.0

    0 5 10 15 20 25 30

    No

    rma

    lize

    d T

    um

    or

    Vo

    lum

    e

    Days after treatment

    Control

    PEG-GNR

    C-GNR

    Cetuximab

    Rad

    Cetuximab + Rad

    PEG-GNR + Rad

    C-GNR + Rad

    ~25nm

    conjugated

    nanorod

    Progressive

    intracellular

    accumulation

    Incd oxidative stress

    Incd DNA damage

    XRT

    ~120nm

    Thermo-

    sensitive

    liposome

    with gold

    XRT FUS PEG

    AuNp

    Aqueous core

    Phospholipid

    bilayer

    Hydrophobic region

    12

    0-1

    30

    nm

    0 3 6 9 12 15 18 21 24 27 300

    50

    100

    150

    200

    250

    300

    350

    400

    Control

    HT

    TSLAuNp

    Rad

    TSLAuNp + Rad

    TSLAuNp + HT+ Rad

    Days

    No

    rmali

    zed

    tu

    mo

    r vo

    lum

    e

    Deep penetration

    of nanoparticles

    Larger particles for vascular-targeted applications (thermo-

    ablation, hyperthermia, vascular imaging)

    Smaller particles for parenchymal applications (imaging,

    targeted payload delivery)

    Combinations of above