1
Nanoparticles in cancer medicine –
a physician’s 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Krishnan lab, unpublished data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)
γ 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
Inc’d oxidative stress
Inc’d 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
• Unresolved issues related to clinical translation
Summary
14
Patients receiving radiation therapy for cancer
~60% of all patients receive radiation therapy
Often, standard doses of radiation therapy are unable
to cure the tumor but higher doses cannot be given due
to high risk of side effects from overdosing adjacent
normal organs
Can one give the same (standard) dose of radiation to
the tumor but make it behave like a higher dose of
radiation?
The target population
We need new approaches
Pipeline Breakdown According to
Number of Drugs
Marketed# 93
Registered# 1
Pre-registration# 5
Phase III# 47
Phase II# 103
Phase I# 62
Preclinical# 73
No Data# 5
Suspended# 7
Ceased# 150
A new radiosensitization strategy
2 µ 500 nm
15
What nanoparticles work best?
Bland?
Spicy?
Spheres
Rods
Triangles
20 nm
20 nm
What nanoparticles work best?
Where do we stand today?
Prasanna PG, et al. Rad Res 2015: 184(3):235-248.
Courtesy: Gabriel Sawakuchi Courtesy: Jan Schuemann
16
Roadmap to the clinic
Krishnan lab Parmesh Diagaradjane
Amit Deorukhkar
Edward Agyare
Dev Chatterjee
Shanta Bhattarai
Pankaj Singh
Jihyoun Lee
Aaron Brown
Kevin Kotamarti
Nga Diep
Krystina Sang
Jacobo Orenstein Cardona
Norman Colon
Hee Chul Park
Brook Walter
Imaging Physics John Hazle
Jason Stafford
Andrew Elliott
UT Austin James Tunnell
Raiyan Zaman
Priya Puvanakrishnan
Jaesook Park
Georgia Tech Sang Cho
Seong-Kyun Cheong
Bernard Jones
Nanospectra Glenn Goodrich
Don Payne
Jon Schwartz
James Wang
Texas Southern Univ Huan Xie
Funding NIH - KL2, R21 x 2, R01 x 2, U01, T32
DoD, CPRIT, ANH pre-center grant, Shell
UT Cntr Biomed Engg, Hitachi, FUSF, MDACC
Acknowledgements
Baylor Jeffrey Rosen
Rachel Atkinson
Amit Joshi
Rice
Naomi Halas
17
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