Dosimetric optimization of interstitial gene therapy delivery systems
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Dosimetric Optimization of Interstitial Gene Therapy Delivery Systems. Kenneth H. Wong 1 , PhD; Mira Jung 1 , PhD; Anatoly Dritschilo 1 , MD; G. Larry Maxwell 2 , MD,. The Gynecologic Disease Program 1 Georgetown University Med. Ctr. 2 Walter Reed Army Med. Ctr.

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Dosimetric optimization of interstitial gene therapy delivery systems

Dosimetric Optimization of Interstitial Gene Therapy Delivery Systems

Kenneth H. Wong1, PhD; Mira Jung1, PhD;

Anatoly Dritschilo1, MD; G. Larry Maxwell2, MD,

The Gynecologic Disease Program

1Georgetown University Med. Ctr.

2Walter Reed Army Med. Ctr.


Limits on current cancer therapy
Limits on Current Cancer Therapy Delivery Systems

  • 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 BSEC

Feb 18, 2009


Limits on current cancer therapy1
Limits on Current Cancer Therapy Delivery Systems

  • Radiation therapy can be highly conformal, but also biologically indiscriminate.

  • How can we devise an effective combination therapy?

cyberknifeinstamford.com

graveslab.stanford.edu

Oak Ridge National Lab BSEC

Feb 18, 2009


Geneseed concept
GeneSeed Concept Delivery Systems

  • 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.

Oak Ridge National Lab BSEC

Feb 18, 2009


Geneseed concept1
GeneSeed Concept Delivery Systems

pIEX-1

TNF-α

  • GeneSeeds were originally designed to express constitutively (always on).

Radiation Inducible Promoter

The GeneSeed payload can now be linked to different promoters, allowing enhanced control of gene expression.

Oak Ridge National Lab BSEC

Feb 18, 2009


Geneseed effect on tumor growth
GeneSeed Effect on Tumor Growth Delivery Systems

Oak Ridge National Lab BSEC

Feb 18, 2009


Brachytherapy tools
Brachytherapy Tools Delivery Systems

www.micknuclear.com

www.oncura.net

www.cfpc.ca/cfp

Oak Ridge National Lab BSEC

Feb 18, 2009


Ultrasound imaging
Ultrasound imaging Delivery Systems

Oak Ridge National Lab BSEC

Feb 18, 2009


Cone beam ct guidance
Cone beam CT guidance Delivery Systems

  • Siemens

  • DynaCT

Oak Ridge National Lab BSEC

Feb 18, 2009


Seed geometry
Seed Geometry Delivery Systems

r

z

θ

L

D

d

z1

Oak Ridge National Lab BSEC

Feb 18, 2009


Diffusion model
Diffusion Model Delivery Systems

  • Divide region into 100 micrometer voxels.

  • Compute concentration gradients.

  • Transport plasmid, repeat

Oak Ridge National Lab BSEC

Feb 18, 2009


Model results
Model results Delivery Systems

Oak Ridge National Lab BSEC

Feb 18, 2009


Monte carlo model
Monte Carlo Model Delivery Systems

  • Vector as a particle with randomly chosen direction and path length.

  • Opening in the seed modeled as a line source of vectors.

Oak Ridge National Lab BSEC

Feb 18, 2009


Reporter gene expression
Reporter gene expression Delivery Systems

Excised tumor

Microtome slices for microscopy & immunohistochemistry

Oak Ridge National Lab BSEC

Feb 18, 2009


Gene v radiation seed
Gene v. Radiation Seed Delivery Systems

Oak Ridge National Lab BSEC

Feb 18, 2009


Dose simulations effect of seed misplacement
Dose Simulations – Effect of Seed Misplacement Delivery Systems

1

0

2

3

Oak Ridge National Lab BSEC

Feb 18, 2009


Mechanical analysis
Mechanical Analysis Delivery Systems

Applied Loads

Hollow Cylinder

Truss

Perforated Cylinder

Oak Ridge National Lab BSEC

Feb 18, 2009


opticsplanet.com Delivery Systems

Westerlund Telescope, Uppsala Univ.

www.astro.uu.se/grundutb/wt/

Oak Ridge National Lab BSEC

Feb 18, 2009


Finite element model
Finite element model Delivery Systems

Oak Ridge National Lab BSEC

Feb 18, 2009


Discussion
Discussion Delivery Systems

  • 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 BSEC

Feb 18, 2009


Summary
Summary Delivery Systems

  • 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

Oak Ridge National Lab BSEC

Feb 18, 2009


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