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Nanoparticles for Medical and Surgical Tumor Therapy

Nanoparticles for Medical and Surgical Tumor Therapy . James M. Provenzale, MD. Departments of Radiology, Oncology and Biomedical Engineering Emory University School of Medicine and Department of Radiology Duke University Medical Center. Disclosures. Bayer Pharmaceuticals Advisory Board.

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Nanoparticles for Medical and Surgical Tumor Therapy

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  1. Nanoparticles for Medical and Surgical Tumor Therapy James M. Provenzale, MD Departments of Radiology, Oncology and Biomedical Engineering Emory University School of Medicine and Department of Radiology Duke University Medical Center

  2. Disclosures • Bayer Pharmaceuticals Advisory Board • Research Funding from Bayer Pharmaceuticals and GE Healthcare

  3. Aims • Discuss medical uses of nanoparticles • Show how nanoparticles and fluorescent molecules can be used for intraoperative imaging

  4. Delivery Vehicles • Chemotherapy or radiation therapy • Other therapeutic drugs • Gene therapy • Materials for tissue engineering

  5. Liposomes • vesicles having a phospholipid bilayer membrane and an aqueous core  S. Leary. Neurosurgery 2006; 58:1009-1025

  6. Liposomes • Some liposomal chemotherapy formulations are already in clinical use • Liposomal doxorubicin for Kaposi’s sarcoma and ovarian cancer • Opportunity exists for targeted delivery

  7. Targeted Imaging Subcutaneous implantation of glioma tumor-targeted nanoparticles non-targeted nanoparticles C. Sun et al. Small 2008; 4:372-379

  8. Multi-functional Capability S. Leary. Neurosurgery 2006; 58:1009-1025

  9. Liposomes • Can be made modified for delivery of contents solely at target-site - disruption by ultrasound focused solely at the tumor - disruption by heat applied at tumor site - Responsive to local environmental conditions (e.g., pH, hypoxia)

  10. Tissue Regeneration VM Tysseling-Mattiace. J Neurosci 2008; 28:3814-3823 G Silva. Nat Rev Neurosci 2006; 7:65-74

  11. Multiple Sclerosis Imaging: Targeting myelin debris Nanoscaffold with axonal nutrients Treatment: Decrease inflammatory response

  12. Therapeutic Uses • Thermal ablation • Intra-operative guidance for improving surgical margins

  13. Thermal Ablation Mice bearing squamous cell carcinoma implants Control injection- saline, no nanoparticles Intratumoral injection of gold nanoparticles Intravenous injection of gold nanoparticles E. Dickerson. Cancer Letters 2008; 269:57-66

  14. Thermal Ablation Intratumoral injection of gold nanoparticles Signal proportional to number of particles within tumor Intravenous injection of gold nanoparticles Control injection- no nanoparticles

  15. Thermal Ablation Intratumoral injection of gold nanoparticles Temperature change, 0 C Control injection, no nanoparticles

  16. Tumor Growth after Ablation Control group- no nanoparticles Intravenous injection of nanoparticles Intratumoral injection of nanoparticles

  17. Findings after Thermal Ablation Silver staining for nanoparticles Gross pathology Hematoxylin-eosin L. Hirsch, et al. PNAS 2003; 100:13549-13554

  18. Iron Oxide Particles • Ultrasmall paramagnetic iron oxide particles that can be used for imaging • Already in human use JH Lee et al. Angew Chem Int Ed Engl 2006; 45:8160-8162

  19. Intra-operative Imaging • Intra-operative 0.3T pre-resection • Intra-operative 0.3T post-resection

  20. Intraoperative Imaging Problems: • High cost of MR scanners • Usually not portable • Increase surgical time • Do not provide real-time feedback

  21. Real-time Intraoperative Imaging • Fluorescent molecule as a contrast agent • Passive accumulation in tumor hours after infusion • Laser excitation • Fluorescence depicted as color image or spectral wave form

  22. Real-time Intraoperative Imaging

  23. Improving Surgical Margins • Subcutaneous breast cancer xenograft • Resected tumor without optical imaging, to simulate conventional surgery

  24. Improving Surgical Margins • Tumor cells had been modified to contain luciferase enzyme • After injection of luciferin, tumor could be detected using bioluminescence imaging

  25. Positive Tumor Margin

  26. Improving Surgical Margins Optical Imaging

  27. Surgery in Large Animals Naturally occurring sarcoma in a dog Resection 24 hours after infusion of fluorescent contrast agent

  28. Optical Imaging of Tumor Regions of high signal intensity At histology, all sites were + for tumor

  29. Normal Tissue Region of normal signal intensity

  30. Normal Tissue Region of normal signal intensity

  31. Positive Tumor Margins Region of high signal intensity

  32. Imaging-Histology Correlation • Canine patient with thyroid carcinoma Imaging Histology • Black- low signal (negative) • Normal tissue- square • Blue-intermediate signal (negative) • Tumor- circle • Red- high signal (positive)

  33. Imaging-Histology Correlation • Black square- true negative • Red circle- true positive • Blue square- true negative • Blue circle- false negative

  34. Imaging-Histology Correlation • 4 true negatives • 4 true positives • 1 false negative

  35. Summary • Nanoparticles have capabilities to delivery drug therapy and materials for tissue regeneration • Nanoparticles, alone or with fluorescent contrast agents, can provide a means to improve surgical results

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