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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 • 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 Delivery Vehicles • Chemotherapy or radiation therapy • Other therapeutic drugs • Gene therapy • Materials for tissue engineering Liposomes • vesicles having a phospholipid bilayer membrane and an aqueous core S. Leary. Neurosurgery 2006; 58:1009-1025 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 Subcutaneous implantation of glioma non-targeted nanoparticles tumor-targeted nanoparticles C. Sun et al. Small 2008; 4:372-379 Multi-functional Capability S. Leary. Neurosurgery 2006; 58:1009-1025 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; 28:38143823 Multiple Sclerosis Imaging: Targeting myelin debris Treatment: Decrease inflammatory response Nanoscaffold with axonal nutrients Therapeutic Uses • Thermal ablation • Intra-operative guidance for improving surgical margins Thermal Ablation Mice bearing squamous cell carcinoma implants Control injectionsaline, no nanoparticles Intratumoral injection of gold nanoparticles Intravenous injection of gold nanoparticles E. Dickerson. Cancer Letters 2008; 269:57-66 Thermal Ablation Intratumoral injection of gold nanoparticles Signal proportional to number of particles within tumor Intravenous injection of gold nanoparticles Control injectionno nanoparticles Thermal Ablation Intratumoral injection of gold nanoparticles Temperature change, 0 C Control injection, no nanoparticles Tumor Growth after Ablation Control group- no nanoparticles Intravenous injection of nanoparticles Intratumoral injection of nanoparticles Findings after Thermal Ablation Hematoxylineosin Gross pathology Silver staining for nanoparticles L. Hirsch, et al. PNAS 2003; 100:13549-13554 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 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 • Passive accumulation in tumor hours after infusion • Laser excitation • 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 Imaging • Black- low signal (negative) • Blue-intermediate signal (negative) • Red- high signal (positive) Histology • Normal tissuesquare • Tumor- circle Imaging-Histology Correlation • Black squaretrue negative • Red circletrue positive • Blue squaretrue negative • Blue circlefalse negative Imaging-Histology Correlation • 4 true negatives • 4 true positives • 1 false negative 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
