Nanoparticles for Medical and Surgical Tumor Therapy
Departments of Radiology, Oncology and Biomedical EngineeringEmory 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; 58:1009-1025
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
tumor-targeted nanoparticles
C. Sun et al. Small 2008; 4:372-379
non-targeted nanoparticles
Subcutaneous implantation of glioma
S. Leary. Neurosurgery 2006; 58:1009-1025
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; 28:3814-
3823
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; 100:13549-13554
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; 45:8160-8162
• 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
