1. What is Cancer? What is Cancer? Cancer is the evolution of a cell that grows uncontrollably11000 1 million 1 billion 1 trillion Number of cancer cells

2. This evolution results from changes in the cells’ DNA Like a combination lock, many genes must be affected for a cell to become cancer… …but there are many combinations

3. 3 major challenges where nanotechnology is needed Cancer comes from our cells – domestic terrorist!Cancer comes from our cells – domestic terrorist! Cancers are different from patient to patientCancers are different from patient to patient Cancers continue to change as they growCancers continue to change as they grow

4. Challenge #1: Cancer comes from our cells – domestic terrorist! Bacteria & viruses = easy to spot Cancer = difficult to detect, difficult to treat

5. Challenge #2: Cancers are different from patient to patient Each tumor is like a salad from a salad bar They all have a unique combination of ingredients (DNA errors)

6. Challenge #3: Cancers continue to change as they grow Tumors are playing the lottery, trying to get the right combination to be able to spread (metastasize) If a tumor is detected too late, it has probably already won Number of cancer cells 11000 1 million 1 billion 1 trillion

7. Peptide library on beads Normal serum Cancer serum Using the body’s own defenses as an early warning system – immune monitoring of tumors Brad Messmer, Thomas Kipps, Dennis Carson green red A B C D E F sort Parts of the tumor are oxygen deprived and die

8. Cleavable peptide lights up spontaneous mammary tumors in MMTV-polyoma middle T, iNOS -/- mice Tumor contrast ~6 Live anesthetized mouse 55 min after tail vein injection Emmi Olson; Dr. Lesley Ellies (UCSD) Tumor-specific Uptake of nanoparticles- Roger Tsien protease Maximal cellular binding/uptake Minimal cellular binding/uptake

9. Small nonsticky nanoparticles Mutually adherent aggregates Tumor- specific proteases 20-200 KDa Tumor-specific Nanoparticle Agregation Nanoparticles are actually much smaller than cells R.Y. Tsien & R. Mattrey (UCSD); P. Daugherty (UCSB)

10. Tumor Mass αvβ3 -negative αvβ3-positive Nanoparticle smart bombs attack blood vesicles which nourish metastatic tumors -David Cheresh

11. Nanoparticle targets  3 and delivers mutant Raf gene to tumor- associated vessels + + + + + + + + + + + + + + + + ++ +++ +++ + +++ + + Cationic lipid  -Targeting Ligand - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Hood et al., Science 2002 After treatment Lung tumor before treatment Nanoparticle Smart Bombs for Metastatic Solid Tumors -David Cheresh 2 related simple drugs against  3 in Phase II trials (Celengtide –Merck Germany brain cancer) and Phase III trails (Vitaxin MedImmune for melanoma and prostate cancer)

12. Liposome Encapsulated Virus particles Trogler, Mattrey, Kummel Phase I: Use emulsion and ultrasonic processing of liposomes to construct micron size ultrasonic imaging bubbles. Phase II: Incorporate adenoviral nanoparticles within nanosized liposome shells for targeting CLL and lymphatic tumors. Phase III: Incorporate surface receptors for tumor-specific targeting on the liposome mothership surface. Y Y Y Y Y Y Y Y Y Y Liposome or albumin shell filled with PFC vapor and adenoviral or nanoparticle pay- load with surface targeting receptors Ultrasound image from the Mattrey Lab showing vasculature of lung tumor with PFC filled bubbles. Vascular used to classify tumors

13. Cancer cell detector for surgical margins in breast cancer A. Kummel, W. Trogler, I. Schuller, S. Esener,, B. Messmer, D. Messmer, S. Blair, J. Wang-Rodriguez Cell array to automate touch prep of surgical margins in breast cancer and to detect changes in phenotype with disease progression Primary detection via size and shape on  -MUC1 coated array Secondary phenotyping with quantum dot labeled antibodies

14. (Nature Biotechnology Vol. 16, 541- 546, 1998) Top White bacteria are separated from red blood cells by AC electric fields applied to circular electrodes Bottom 2 types of cells are separated by AC electric field Dielectrophoresis (DEP) Separation in Blood Samples – Mike Heller Can be enhanced with cancer specific nanoparticle markers. Goal – find rare cancer cells in blood