dosimetric optimization of interstitial gene therapy delivery systems
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1
Dosimetric Optimization of Interstitial Gene Therapy
Delivery Systems
The Gynecologic Disease Program
1Georgetown University Med. Ctr.
2Walter Reed Army Med. Ctr.
Kenneth H. Wong1, PhD; Mira Jung1, PhD;
Anatoly Dritschilo1, MD; G. Larry Maxwell2, MD,
Oak Ridge National Lab BSECFeb 18, 2009
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Limits on Current Cancer Therapy
Cancer is fundamentally a genetic disease.
Gene therapy is biologically targeted, but distribution is difficult to control.
Bystander and systemic effects pose major limitations.
Oak Ridge National Lab BSECFeb 18, 2009
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Limits on Current Cancer Therapy
Radiation therapy can be highly conformal, but also biologically indiscriminate.
How can we devise an effective combination therapy?
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Oak Ridge National Lab BSECFeb 18, 2009
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GeneSeeds are small hollow titanium tubes which can be implanted like brachytherapy seeds.
Multiple seeds with regular spacing enables treatment of larger regions or organs.
GeneSeed Concept
Oak Ridge National Lab BSECFeb 18, 2009
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GeneSeeds were originally designed to express constitutively (always on).
GeneSeed Concept
pIEX-1 TNF-α
The GeneSeed payload can now be linked to different promoters, allowing enhanced control of gene expression.
Radiation Inducible Promoter
Oak Ridge National Lab BSECFeb 18, 2009
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GeneSeed Effect on Tumor Growth
Oak Ridge National Lab BSECFeb 18, 2009
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Brachytherapy Tools
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Oak Ridge National Lab BSECFeb 18, 2009
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Ultrasound imaging
Oak Ridge National Lab BSECFeb 18, 2009
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Cone beam CT guidance
SiemensDynaCT
Oak Ridge National Lab BSECFeb 18, 2009
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Seed Geometry
L
D
d z1
θ
z
r
Oak Ridge National Lab BSECFeb 18, 2009
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Diffusion Model
2,
Dt
DJ
1. Divide region into 100 micrometer voxels.
2. Compute concentration gradients.3. Transport plasmid, repeat
Oak Ridge National Lab BSECFeb 18, 2009
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Model results
100
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200 200300 300
400 400
500
500600
600700 700
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900
1000
Transverse
Axi
al
Diffusion from Seed face
20 30 40 50 60 70 800
5
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35
Oak Ridge National Lab BSECFeb 18, 2009
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Monte Carlo Model
1. Vector as a particle with randomly chosen direction and path length.
2. Opening in the seed modeled as a line source of vectors.
Oak Ridge National Lab BSECFeb 18, 2009
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Reporter gene expression
Microtome slices for microscopy &
immunohistochemistry
Excised tumor
Oak Ridge National Lab BSECFeb 18, 2009
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Gene v. Radiation Seed
Radioactive Seed Dosimetry Profile
1
10
100
1000
10000
0 1 2 3 4 5 6
Distance from Source [mm]
Do
se R
ate
[cG
y/hr
]
Oak Ridge National Lab BSECFeb 18, 2009
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Dose Simulations – Effect of Seed Misplacement
0 1
32
Oak Ridge National Lab BSECFeb 18, 2009
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Mechanical Analysis
Applied Loads
Hollow Cylinder
Perforated Cylinder
Truss
Oak Ridge National Lab BSECFeb 18, 2009
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Westerlund Telescope, Uppsala Univ.
www.astro.uu.se/grundutb/wt/
Oak Ridge National Lab BSECFeb 18, 2009
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Finite element model
Oak Ridge National Lab BSECFeb 18, 2009
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Discussion
Inhomogeneity represents a major challenge, as tissues can be very different.
Diffusion weighted MRI may be useful in providing additional treatment planning data.
Could create a tough (interesting) problem for dose optimization.
Oak Ridge National Lab BSECFeb 18, 2009
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Summary
GeneSeeds represent a promising anti-cancer combination therapy
Dosimetry models have been constructed
– Next step: Validation in large animal model
Modified cylinder or truss is compatible with mechanical needs
– Challenge may be material retention
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