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Targeted Intratumoral Therapy Using Nanoparticles: Modeling and Application

Explore the efficacy of nanoparticles for targeted drug delivery to tumors at varying length scales. Learn about nanoparticle synthesis, surface functionality control, cell penetration mechanisms, and bacteria-mediated therapeutic production in tumor microenvironments.

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Targeted Intratumoral Therapy Using Nanoparticles: Modeling and Application

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  1. Nanoparticles for Nanomedicine Neil S. Forbes Nanotechnology Institute University of Massachusetts, Amherst July 24, 2009 University of Massachusetts Chemical Engineering

  2. Targeted Delivery to Tumors

  3. Many Different Length Scales 10cm 100mm 1cm 1mm

  4. Relative Size of Nanoparticles Nanoparticle with a 2 nm core and an octanethiol functionalized monolayer

  5. Making Gold Nanoparticles • AuCl4- salts are reduced using NaBH4 in the presence of thiol capping ligands • The core size of the particles formed can be varied from <1 nm to ~ 8 nm • The surface functionality can be controlled through the choice of thiols

  6. Fluorophores and Drugs Selectively Dissociate Inside Cells

  7. Control of Surface Charge

  8. Plug Cylindroid Well Plate 100 mm Microscope Objective Investigating Delivery Using Cylindroids Viable Dead

  9. Nanoparticles in Cylindroids

  10. y x Nanoparticle Diffusion b a 4hrs 24hrs d c D×107 cm2/sec

  11. Modeling Particle Diffusion

  12. Predicting Behavior in Tumors

  13. Delivery of Doxorubicin

  14. Paracellular Transcellular How Does Particle Charge Affect Tissue Penetration? A B Cells

  15. Engineering Approach:Targeted Intratumoral Therapy • Quantify tumor microenvironments • Develop vectors to target tumor quiescence Necrotic Quiescent Proliferating Therapeutic

  16. Microenvironments in Cylindroids Viability Acridine Orange Scale bar is 100 µm Kasinskas, Forbes. 2006.Biotech Bioeng, 94:710

  17. Bacteria Accumulate in Mouse Tumors

  18. Bacteria are Tiny Robot Factories • Target specific molecular signals • Can controllably produce therapeutics

  19. Plug Polycarbonate Lid Cylindroid Culture Media 96-well plate Well Plate 100 mm P Q N Microscope Objective Bacterial Accumulation in Cylindroids Cylindroids mimic tumor microenvironments

  20. Control of Cytotoxicity • Inject modified bacteria • Induce peptide with radiation

  21. Tumor Growth and Mouse Survival PBS Control Bacteria Cytotoxic Bacteria PBS + 2Gy Control Bacteria + 2Gy Cytotoxic Bacteria + 2Gy Median survival doubles from 14.0 to 26.0 days Bacteria + Radiation Control + 2Gy PBS + 2Gy Cytotoxic Bacteria Control Bacteria PBS

  22. Effect of Double Dose • Delayed growth 30.3 days • 30-day survival increased from 0% to 100%

  23. Acknowledgements Graduate Students Adam St. Jean Charley Swofford Bhushan Toley Raja Venkatasubramanian Miaomin Zhang Undergraduate Students Brett Babin Jason Lee Marissa McGarry Alumni Dr. Sabha Ganai, MD PhD Surgical Oncology, Baystate Medical Center Dr. Rachel Kasinskas, PhD Dr. Byoung-jin Kim, PhD Colin Walsh Collaborators Michael A Henson, PhD Richard B Arenas, MD Vincent M Rotello, PhD Funding NIH, NSF Susan G. Komen For the Cure UMass Center for Biomedical Research Rays of Hope, Springfield, MA

  24. A B C Cells

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