Download Graduate Category: Health Science Degree Level: PhD Abstract ID# 1298

Graduate
Category: Health Science
Degree Level: PhD
Abstract ID# 1298
Curing cancer: Using MRI to understand how and why therapeutic nanoparticles work
Ju Qiao, Liam Timms, Codi Gharagouzloo, Zihang Fang, Joseph Nneji, Kristofer Patel, Paige Baldwin, Anne L. van de Ven, Srinivas Sridhar
Experimental design
Visualization of nanoparticles in tumors
24hr accumulation
(4hr vehicle)
No ferumoxytol
(No treatment)
We have developed a quantitative ultra-short time-to-echo
contrast-enhanced (QUTE-CE) magnetic resonance
imaging (MRI) technique to quantify nanoparticle delivery in
blood vessels and tissues using FDA-approved iron oxide
nanoparticles as a surrogate. Here we show, for the firsttime, that this cutting-edge imaging technique can provide
us with new insights into the mechanisms of nanoOlaparib,
a nanoformulated DNA repair inhibitor.
Visualization of nanoparticles in blood
24hr accumulation
(4hr nanoOlaparib)
T1
T2
Before ferumoxytol
Treatment of prostate cancer using nanoOlaparib
QUTE-CE produces
positive-contrast images
UTE
% nanoparticles
14
1 day
3 months
12
10
0.5mm
8
6
Fig 4. Comparison of different MRI imaging techniques
of ferumoxytol accumulation in a mouse prostate tumor
4
0
10
100
Diameter (nm)
nanoOlaparib is created by inserting
drug into the bilayer of liposomes
1000
nanoOlaparib has a uniform diameter
and is stable with time
Individual nanoparticles are
visualized using TEM
Fig. 1. Characterization of Olaparib nanoformulation
nanoOlaparib alone slows
but does not prevent
tumor growth
6
5
4
3
1
0
7
14
21
Days
28
35
24hr accumulation
(4hr nanoOlaparib)
6
Drug-loaded particles yield
brighter signal than empties
= MORE ACCUMULATION
4
2
0
500
42
1000
1500
UTE voxel intensity (AU)
Inset: Ferumoxytol signal in untreated (L)
and nanoOlaparib-treated (R) tumors
25
Fig. 2. Change in mouse prostate tumor size following treatment
Untreated
10Gy radiation
nanoOlaparib
nanoOlaparib + 10Gy
100
80
% Surviving
8
24hr accumulation
(4hr vehicle)
60
40
nanoOlaparib +
radiation cures
50% of mice
20
0
2
4
6
Weeks
8
10
12
Fig. 3. Mouse survival time following treatment
• What to test next: Does nanoOlaparib increase
its own efficacy by enhancing its own ability to
accumulate in tumors?
References of interest
1) Codi Gharagouzloo et al. Magnetic Resonance in
Medicine. 2015, 74(2): 431-441
2) Yixiang Wang. Quantitative Imaging in Medicine and
Surgery. 2011, 1(1): 35-40
18x signal
enhancement
3) J. C. Brisset, et al. Mol. Imag. Biol. 2011, 13: 672–678
20
4) Y. Okuhata, Adv. Drug Deliv. Rev. 1999, 37:121–137
15
Acknowledgements
10
5
0
1
0
• nanoOlaparib enhances nanoparticle
accumulation in tumors by as much as 18x
2000
Fig. 5. Quantification of UTE signal intensity across the entire
tumor volume following repeat ferumoxytol administration
2
0
empty
control
• QUTE-CE MRI provides quantitative, positivecontrast images of nanoparticle accumulation in
both tumor tissue and tumor vasculature
• nanoOlaparib treatment causes tumors to lose
their resistance to radiation therapy
0
nanoOlaparib +
radiation greatly reduces
tumor growth
% signal-enahnced voxels
with significant accumulation
Fold change in tumor size
Untreated
10Gy radiation
nanoOlaparib
No ferumoxytol
(No treatment)
10
ln (voxel number)
1
7
Fig. 7. Ferumoxytol in the tumor vasculature following
nanoOlaparib administration
What we learned
2
8
After ferumoxytol
2
3
No treatment
4
5
6
Radiation
7
8
9
10
11
nanoOlaparib
Fig. 6. Enhancement of nanoparticle accumulation following
nanoOlaparib administration
This work was supported by the following grants: NSF-DGE-0965843,
NIH HHS/IU54CA151881, CIMIT 13-1807, NIH NCI R01CA082328,
NIH 5 P30 CA06516, and the Mazzone Foundation. The FK01
mouse prostate cancer cells were kindly donated by the Pandolfi
group at the Beth Israel Deaconess Cancer Center