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

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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

  • 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

  • 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

  • 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

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

Oak Ridge National Lab BSEC

Feb 18, 2009


Brachytherapy tools

Brachytherapy Tools

www.micknuclear.com

www.oncura.net

www.cfpc.ca/cfp

Oak Ridge National Lab BSEC

Feb 18, 2009


Ultrasound imaging

Ultrasound imaging

Oak Ridge National Lab BSEC

Feb 18, 2009


Cone beam ct guidance

Cone beam CT guidance

  • Siemens

  • DynaCT

Oak Ridge National Lab BSEC

Feb 18, 2009


Seed geometry

Seed Geometry

r

z

θ

L

D

d

z1

Oak Ridge National Lab BSEC

Feb 18, 2009


Diffusion model

Diffusion Model

  • Divide region into 100 micrometer voxels.

  • Compute concentration gradients.

  • Transport plasmid, repeat

Oak Ridge National Lab BSEC

Feb 18, 2009


Model results

Model results

Oak Ridge National Lab BSEC

Feb 18, 2009


Monte carlo model

Monte Carlo Model

  • 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

Excised tumor

Microtome slices for microscopy & immunohistochemistry

Oak Ridge National Lab BSEC

Feb 18, 2009


Gene v radiation seed

Gene v. Radiation Seed

Oak Ridge National Lab BSEC

Feb 18, 2009


Dose simulations effect of seed misplacement

Dose Simulations – Effect of Seed Misplacement

1

0

2

3

Oak Ridge National Lab BSEC

Feb 18, 2009


Mechanical analysis

Mechanical Analysis

Applied Loads

Hollow Cylinder

Truss

Perforated Cylinder

Oak Ridge National Lab BSEC

Feb 18, 2009


Dosimetric optimization of interstitial gene therapy delivery systems

opticsplanet.com

Westerlund Telescope, Uppsala Univ.

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

Oak Ridge National Lab BSEC

Feb 18, 2009


Finite element model

Finite element model

Oak Ridge National Lab BSEC

Feb 18, 2009


Discussion

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 BSEC

Feb 18, 2009


Summary

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

Oak Ridge National Lab BSEC

Feb 18, 2009


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