Download Slide - Society Of Interventional Radiology

“Seeing” Stem Cells Helps in Fight
Against Peripheral Arterial Disease
Dorota A Kedziorek, MD, Piotr Walczak, MD,
PhD, Yingli Fu, PhD, Frank Wacker, MD,
Dara L Kraitchman, VMD, PhD
Johns Hopkins University
School of Medicine
Russell H. Morgan Department of Radiology and
Radiological Science
Baltimore, MD
Presenter Disclosure Information
I will discuss off label use and/or investigational
use of contrast agents in my presentation.
Financial Relationships to disclose:
• Bayer Schering Pharma AG
• Boston Scientific Corporation
• Surgi-vision, Inc.
Peripheral Arterial Disease (PAD)
• PAD affects ~8-12 million
Americans.
• 1 in 5 patients with critical
limb ischemia have severe
enough disease to be
ineligible for conventional
medical or surgical
revascularization therapy.
• Gene, protein, and cellular therapies offer an
alternative means to attack the response to
occlusion by “therapeutic arteriogenesis.”
How to create new blood vessels?
Problems with Current Cell Therapy
1. Cannot “see” where cells are injected.
Needles marking injection sites
Problems with Cell Therapy
1. Cannot “see”
where cells are
injected.
2. Large number of
cells die after
administration
Solution: Place Cells in “Seaweed Bubble”
APA ≡Alginate-poly-L-lysine-alginate
Lim and Sun, Science 1980
Biocompatible
- Provides surface for
cell adhesion
Selective permeability
- Blocks antibody and
cellular destruction –
good for transplanted
O2, Glu donor cells
VEGF, PGE2,
- Permits diffusion of
IL-8, IL-6, HGF, etc. nutrients and waste
products.
IgG, IgM
Courtesy: Ming Chen
What If Imaging Visible Capsules Were
Possible?
“Liquid Oxygen”
•Trimodal Imaging Agent
•Bromine – X-ray
•Perfluorocarbon – U/S
•19F - MRI
Imaging Sensitivity to PFOB Caps
5
10
25
capsules/dot:
c-arm CT
19F
MRI
2 cm
Fu et al., SCMR 2009
X-ray Monitoring of PFOB Caps Delivery in
a Rabbit PAD Model
Immediately after injection
Unlabeled
PFOB Caps
Five weeks post-injection
Can see the PFOB Cap,
but is the cell alive?
Bioluminescence Imaging
Luciferin
Oxyluciferin
Luciferase
Bioluminescence Signal
ATP
High
Light
Cells expressing luciferase
Low
A
Bioluminescence imaging of Embryonic
Stem Cells
P/s/cm2/sr
P/s/cm2/sr
P/s/cm2/sr
P/s/cm2/sr
10
10
10
10
10
8
8
8
8
8
6
6
6
6
6
4
Control
P/s/cm2/sr
4
×103
4
×105
×105
4
×106
4
2
2
2
2
2
0
0
0
0
0
Day 5
Day 10
×106
Cao F, et al. Circulation 2006;113:1005-14
Reporter Probe Dose Intravenous Injection:
•Rabbit =10 X Rat!
•Patient = 150 X Rat!
Animal study #1
Immediately post injection
24 hrs post injection
PFOB encapsulated transfected MSCs
“Naked” transfected MSCs
“Naked” transfected MSCs
How to Administer Reporter Probe?
BLI
Immediately post injection
Pure alginate caps
PFOB encapsulated
transfected MSCs
DynaCT – 24 hrs post
Using Interventional Radiology to Guide
Reporter Probe Injections
Immediately post injection
C-arm CT Targeting
Pure alginate caps
PFOB encapsulated
transfected MSCs
24 hrs post injection
PFOB encapsulated
transfected MSCs
48 hrs post injection
PFOB encapsulated
transfected MSCs
Seaweed Plus Liquid Oxygen
Plus Firefly “Brew”
Seaweed (Protanal®)
Liquid
Oxygen
(Oxygent®):
_
Firefly
• Happy Cells
• FDA-approved agents
in bubble
• Better able to survive
to create new blood
vessels for PAD
• Visible by X-ray for
Interventional
Radiologist to tailor
therapy
Acknowledgments
•
•
•
•
•
Aravind Arepally
Brad Barnett
Jeff Bulte
Lawrence Hofmann
Gary Huang
•
•
•
•
•
•
•
Mark Pittenger
Randall Young
Christine Lorenz
Tina Ehtati
Steve Shea
Wesley Gilson
Robert Krieg
NIH R01-HL63439, R01-HL73223, K08 EB004348,
R21-HL89029, R01-EB007825, and MD-SCRFII-0399-00
Conclusions
•
“Seaweed plus liquid oxygen plus firefly brew”:
 Enhanced cell viability
 Enables visualization with X-ray and Optical
Imaging
• C-arm CT provides a minimally invasive method
to target the reporter probe for localized
injections to our X-ray visible capsules to
reduce dose of reporter probe.
• First demonstration of X-ray visible stem cell
therapeutic with ability to measure
cell viability by imaging.
Trimodal Imaging
MRI
c-arm CT
US