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Dosimetric Optimization of Interstitial Gene Therapy Delivery Systems

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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  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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

  6. GeneSeed Effect on Tumor Growth Oak Ridge National Lab BSEC Feb 18, 2009

  7. Brachytherapy Tools www.micknuclear.com www.oncura.net www.cfpc.ca/cfp Oak Ridge National Lab BSEC Feb 18, 2009

  8. Ultrasound imaging Oak Ridge National Lab BSEC Feb 18, 2009

  9. Cone beam CT guidance • Siemens • DynaCT Oak Ridge National Lab BSEC Feb 18, 2009

  10. Seed Geometry r z θ L D d z1 Oak Ridge National Lab BSEC Feb 18, 2009

  11. Diffusion Model • Divide region into 100 micrometer voxels. • Compute concentration gradients. • Transport plasmid, repeat Oak Ridge National Lab BSEC Feb 18, 2009

  12. Model results Oak Ridge National Lab BSEC Feb 18, 2009

  13. 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

  14. Reporter gene expression Excised tumor Microtome slices for microscopy & immunohistochemistry Oak Ridge National Lab BSEC Feb 18, 2009

  15. Gene v. Radiation Seed Oak Ridge National Lab BSEC Feb 18, 2009

  16. Dose Simulations – Effect of Seed Misplacement 1 0 2 3 Oak Ridge National Lab BSEC Feb 18, 2009

  17. Mechanical Analysis Applied Loads Hollow Cylinder Truss Perforated Cylinder Oak Ridge National Lab BSEC Feb 18, 2009

  18. opticsplanet.com Westerlund Telescope, Uppsala Univ. www.astro.uu.se/grundutb/wt/ Oak Ridge National Lab BSEC Feb 18, 2009

  19. Finite element model Oak Ridge National Lab BSEC Feb 18, 2009

  20. 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

  21. 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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