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

Disclosures Bayer Pharmaceuticals Advisory Board Research Funding from Bayer Pharmaceuticals and GE Healthcare

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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: Already in human use

Intra-operative Imaging  Intra-operative 0.3T pre-resection  Intra-operative 0.3T post-resection

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

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

Real-time Intraoperative Imaging

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

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

Positive Tumor Margin

Improving Surgical Margins Optical Imaging

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

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

Normal Tissue Region of normal signal intensity

Normal Tissue Region of normal signal intensity

Positive Tumor Margins Region of high signal intensity

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

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

Imaging-Histology Correlation 4 true negatives 4 true positives 1 false negative

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