1. Applications of Nanotechnology to Central Nervous System Imaging 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 Indicate the ways nanotechnology will fundamentally change the role of the radiologist Explain uses of nanoparticles in medical imaging

4. Nanotechnology Development of materials and devices on the nanometer scale (i.e., 1-100 nm) Designed for manipulation of physical, chemical or biological processes

5. Why Nanotechnology? Many aspects of nanomedicine are imaging-based A new, important field of medicine (nanomedicine) is emerging Radiologists need nanotechnology Nanotechnology needs radiologists

6. Nanoparticles Solid colloidal particles on the nm scale Usually 20-50 nm in diameter Frequently composed of insoluble polymers

7. Size Scale Similar in size to a virus 10 μm (10,000) nm JH Lee et al. Angew Chem Int Ed Engl 2006; 45:8160-8162

8. Micelles Dendrimers Types of Nanoparticles Liposomes Iron oxide particles Quantum dots

9. Spherical aggregates with hydrophilic regions facing outward and hydrophobic portions face inward Micelles  S. Leary. Neurosurgery 2006; 58:1009-1025 Drugs can be placed internally

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

11. 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

12. Susceptibility effect on T2*- weighted images Iron Oxide Particles Increased signal intensity on T1-weighted images JH Lee et al. Angew Chem Int Ed Engl 2006; 45:8160-8162 T2*-weighted MR image

13.  S. Leary. Neurosurgery 2006; 58:1009-1025 Dendrimers

14. Semiconductor nanoparticles with unique optical and electrical properties Quantum Dots Very high signal intensity (i.e., high SNR) Persistent signal intensity for long periods Light emission is size-dependent (“tunability”)

15. Optical Properties Composition of nanoparticles determines wavelength of light produced after laser is applied C. Loo, et al. Technol Cancer Res Treat 2004; 3:33-40

16. “Tunability” C. Loo, et al. Technol Cancer Res Treat 2004; 3:33-40

17. Multiplex Imaging Multiple nanoparticles of different composition- each directed against a different protein Y. Xing, et al. Nat Protocols 2005; 2:1152-1165

18. Reticuloendothelial system Impediments to Delivery Excellent hepatic imaging agents Blood-brain barrier Non-target delivery

19. Passive Delivery Small number of particles delivered and solely extracellular deposition X Gao, et al. Nat Biotechnol 2004; 22:969-976

20. Targeted Delivery Large number of particles delivered and intracellular deposition Placement of antibodies or other ligands on surface of nanoparticle to enhance deposition at intended target X Gao, et al. Nat Biotechnol 2004; 22:969-976

21. Imaging agents Uses of Nanoparticles Drug delivery vehicles Functional reporters Means of materials transport

22. High signal:noise ratio Imaging Agents Promise of greater sensitivity and specificity Depth penetration of imaging device

23. Multi-modal Targeted Imaging Fluorescent marker (rhodamine dye) Iron-oxide nanoparticles JH Lee et al. Angew Chem Int Ed Engl 2006; 45:8160-8162 Directed against polysialic acids expressed by neuroblastoma cells

24. Multi-modal Targeted Imaging Iron oxide Fluorescence imaging of neuroblastoma cells MR image JH Lee et al. Angew Chem Int Ed Engl 2006; 45:8160-8162 Fluorescent marker

25. Targeted Nanoparticles C. Sun et al. Small 2008; 4:372-379 tumor-targeted superparamagnetic nanoparticles conjugated against chlorotoxin, an important tumoral protein 9L glioma xenograft grown in the flank of a mouse

26. Targeted Imaging C. Sun et al. Small 2008; 4:372-379 non-targeted nanoparticles tumor-targeted nanoparticles

27. Potential Imaging Uses Early tumor detection Physiological imaging for monitoring early disease response Intra-operative imaging (discussed in my Thursday presentation)

28. Iron-Oxide Nanoparticles L. Muldoon et al., AJNR Am J Neuroradiol 27:715–721  Pre-operative 1.5T  Intra-operative 0.3T 24 hours later

29. Indicators of cell or tissue function Functional Reporters Identify important molecules Monitor therapy

30. Functional Reporters (CLIO)-glucose nanoparticles for functional MR imaging Sosnovik DE, Weissleder R. Curr Opin Biotechnol 2007; 18:4-10 Nanoswitch Assembles when glucose concentration is high Concavalin green CLIO-glucose

31. CLIO-Glucose Nanoswitch Low glucose concentration: switch disassembles High glucose concentration: switch assembles

32. Functional Reporters CLIO-glucose nanoswitch Addition of concavalin Nanoswitch disassembled

33. Functional Reporters Assembly and disassembly of the nanoswitch causes changes in transverse magnetization (T2)

34. Tumor Imaging Used to magnify signal induced in molecules placed on surface of nanoparticles gold nanoparticles

35. Tumor Imaging “Reporter” molecule that provides signal produced by light from laser “Reporter” molecules placed on gold nanoparticles

36. Tumor Imaging Raman spectroscopy- laser light produces characteristic signal peaks from molecules Gold amplifies signal 10 15 times “Reporter” molecules on gold nanoparticles Amplification process: “plasmon resonance”

37. Tumor Imaging

40. Summary This field uses very different contrast agents and detection methods A new field of imaging (nano-imaging) is emerging These agents will provide physiological information previously unavailable to scientists and clinicians

41. Tumor Imaging