Gary D. Fullerton, Ph.D., FACR, FAAPM, FISMRM
Malcolm Jones Distinguished Professor of Radiology
ViceVice-Chair for Research
Radiology Department, UTHSCSA
Foundation
for Molecular
Imaging in
Genetic
Research
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•
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Molecular Imaging
Broadly defined as the spatially
and temporally
Molecular Imaging
measured set of measurements of biological processes
3000
at the cellular and molecular level when visualized as an
optical image by the human observer.
Probes or measures
of molecular abnormalities that are
2000
the basis of disease rather than imaging the end product
of these molecular deficiencies.
1000
Molecular imaging has only recently come into clinical
application at the most rudimentary level and most
present research0 is preclinical.
1980
1990
2000
2010
Why is this so? 1970
Year
Is there a role for AAPM members?
Number of Publications/Year
The Fusion of Molecular
Imaging into Clinical
Medicine: A role for
AAPM?
Target Selection for Molecular
Imaging
Diverse genetic error combinations
Disease is highly individual
Diversity offer many biomarkers
Imaging biomarkers – FDA approval
Approval restricts availability
R Weissleder and U
Individualized biomarkers - SLOW
Mahmoud (2001)
Radiology
R Weissleder and U Mahmoud (2001) Radiology
Molecular Imaging Strategy
1. Target Screening – VEGF
Conjugation of DOTA to Antibody
Avastin + Radiolabeling with 64Cu
HOOC
N
N
N
N
HOOC
EDC
O O
HOOC
COOH
sulfo-NHS
pH5.5
COOH
N
N
O N
N
N
O
COOH
HOOC
pH7.5
mAb--NH2
NH--mAb
-
OOC
N
Cu2+
N
N
N
64
HOOC
O
COO-
NH--mAb
HOOC
CuCl2
N
N
pH6.5
N
N
64
HOOC
SO3-
O
COOH
Wipke BT, Wang Z, et al. Nature Immunology, 2002, 3, 366-372.
TARGET ANGIOGENESIS
R Weissleder and U Mahmoud (2001) Radiology
5. Imaging System - Preclinical
Small Animal Models
6.
Target Assessment - PET/CT FDG vs.
64CuCu-Avastin imaging Solid Tumors
Courtesy Dr. Jim WangWang-Radiochemist,
Radiochemist, UTHSCSA
4. Amplification Strategy Liposome Nanoparticle
LiposomesLiposomes- spontaneously forming lipid bilayer spheres used for
drug delivery applications 90nm to 200 nm.
Different surface modifications of liposomes or other nanoparticles
nanoparticles
to optimize biodistribution characteristics.
3. Delivery Barriers – Solid Tumors
1. Excess deposition of ECM and collagen
2. Elevated pressure ~ 20 mmHg
3. Reduced
blood
flow
Possible
Solutions
4. Hypoxia
– resistance
to radiation RX
1. Ultrasound
irradiation
5. Reduced
deliveryhyluronidase
of chemotherapeutics
2. Systemic
6. Heterogeneous
due to barriers
3. Systemicdelivery
collagenase
7. Refractory
to cancer
options
4. Combine
withtherapy
RF abalation
5. Image guided intratumoral delivery
@ Injection
Intratumoral Injection
of 186ReRe-Doxil
SPECT/CT images 4 hours post injection
Xavier Garcia-Rojas, MD
Molecular Imaging + Therapy
Doxil – Pegylated Liposomes
Containing Doxorubicin
+ Avastin
and/or
99mTc
or
+ 186Re
or
+ 188Re
Imaging and Rx of
Small Animal Models
Systemic Therapies:
- Liposomes with Doxorubicin or 186Re
- Designer Molecules
Intratumoral Therapies:
- Radiofrequency Ablation
- Liposomes with Doxorubicin or 186Re
3D Distribution Of Intratumorally
Administered 186Re Doxil
Imaging can
quantitatively
measure drug
delivery and
distribution in tumor
Cancer Drug Targeting
Passive Targeting
Active Targeting
~3X
CHEMODOSIMETRY
is possible but needs
development
Hyper Targeting
~9X
~3 Fold Increase
~45X
~9 Fold Increase
~45 Fold Increase
Anti-Angiogenesis
Antibody
Nanoparticles
Direct ConvectionMediated Injection
of Nanoparticles
Ande Bao, PhD and Xavier Garcia-Rojas, MD
Control
Performance of Percutaneous
Intratumoral Therapy
Treated with Intratumoral
186Re-Doxil
Intratumoral Therapy vs Tumor Size
(avg data only for time points with 100% survival)
Tumor Volume (cm3)
9.00
Control at 8 days after
the start of the treatment
study
30 days Post Treatment
Doxil
6.00
Doxil + RFA
5.00
4.00
Liposomes + RFA
3.00
Doxil + 186Re + RFA
2.00
1.00
Liposomes + 186Re
Liposomes
Doxil + 186Re
Liposomes + 186Re + RFA
0.00
-20
60% maximal tolerated dose
8.00
7.00
0
20
40
60
80
Day
Slide from Xavier Garcia-Rojas and Ande Bao
100
Performance of Systemic Therapy
Comparison of Change in Tumor Volume
Clinical Translation - Prostate
Cancer - 3.0T Dual coil
12.000
Doxil i.v
10.000
Tumor Volume (cm3)
Liposomes i.v
RFA
8.000
RFA+D
RFA+L
6.000
Re+L
Re+D
4.000
RFA+RE+L
RFA+Re+D
2.000
Control
0.000
-10
0
10
20
30
40
50
Days
A.Jung
Molecular 3.0T MRS - 3D CSI
MRI and MR Spectroscopy
Molecular Imaging of Metabolic
Changes
Healthy voxel:
Cancerous voxel:
• Voxel size ~ 0.16 - 0.30 cc’s
A.Jung
A.Jung
Molecular Image-Guided
Tumor Treatment Program
Medical physics is positioned to
develop an image guided tumor
treatment program that can:
1. Percutaneously deliver RX
agents to treatment sites
2. Assess if Rx agents
accumulate at the treatment site
3. Assess if there is early
response or failure to the agents
4. Obtain repetitive functionally
directed biopsies of target
tissues
AAPM Members have an Important
and Challenging Role to Play
Members CAN participate in the design and
testing of new instrumentation for both
preclinical/animal and human uses.
Members CAN use well documented AAPM
methods for developing nationally acceptable
standards and procedures for assuring the
quality of quantitative imaging data.
Members CAN work to assure the quality of data
intended for use by regulatory agencies such as
the FDA to prove the safety and efficacy of new
methods of human medical care.