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

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

5. vesicles having a phospholipid bilayer membrane and an aqueous core Liposomes  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 tumor-targeted nanoparticles C. Sun et al. Small 2008; 4:372-379 non-targeted nanoparticles Subcutaneous implantation of glioma

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

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

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

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

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

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

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

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

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

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

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 Laser excitation Passive accumulation in tumor hours after infusion 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 Black- low signal (negative) Blue-intermediate signal (negative) Red- high signal (positive) Imaging Histology Normal tissue- square Tumor- circle

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