Nanotechnology in Cancer - Dr. Cote


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Dr. Richard Cote of Sylvester Comprehensive Cancer Center presented "New Technologies That Will Have an Impact on Cancer" at the 2011 WellBeingWell Conference in Miami.

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Nanotechnology in Cancer - Dr. Cote

  1. 1. New Technologies That Will Have an Impact on Cancer Sylvester Comprehensive Cancer Center Well-Being Session, April 26, 2011 Richard J. Cote, MD, FRCPath Chair, Pathology Director, Biomedical Nanoscience Institute University of Miami
  2. 2. Length Scales FITC IgG DNA Diameter GFP Virus Colloidal gold Bacterium Animal Cell Plant Cell 0.5nm 5nm 2nm 1nm 50nm 100nm 1  m 10  m 100  m Nanoworld Microworld
  3. 3. Advantages of Going Nano <ul><li>The scale of nanodevices, in particular sensors, allows for construction of devices that can detect thousands of different reactions in an extremely small area . </li></ul><ul><li>Nanoparticles can be applied in targeted therapy and diagnostic imaging . </li></ul><ul><li>Functionalized nanodevices for interaction at the biotic/abiotic interface will provide substantial benefits for implantable systems . </li></ul><ul><li>Nanomaterials have unique physical properties that allow entirely novel approaches to diagnosis, therapy and functional restoration. </li></ul>
  4. 4. Possible Applications of Nanotechnology in Cancer <ul><li>Diagnosis </li></ul><ul><ul><li>Sensitive detection of serum tumor markers using multiplexed nanosensors </li></ul></ul><ul><ul><li>Multimarker evaluation of tissue using Quantum Dots </li></ul></ul><ul><li>Imaging </li></ul><ul><ul><li>Targeted ferromagnetic nanoparticles for MRI </li></ul></ul><ul><li>Therapy </li></ul><ul><ul><li>Targeted nanoparticles for drug delivery </li></ul></ul>
  5. 5. <ul><li>Nanosensors </li></ul>
  6. 6. Limitations of current blood tests for cancer <ul><li>Large sample volume requirements </li></ul><ul><li>Test performed in reference laboratories </li></ul><ul><li>Time consuming </li></ul><ul><li>Expensive </li></ul><ul><li>Variable sensitivity and specificity </li></ul><ul><li>Cannot be multiplexed </li></ul><ul><li>Can only test for one style of analyte (protein / nucleic acid) </li></ul><ul><li>Single tests incapable of screening for cancer </li></ul>
  7. 7. PSA Detection with Bionanosensor In 2 O 3 NW Device SWNT Mat Device
  8. 8. Challenge in Building and Using Nanosensor Devices: Need microfluidics 24 Sensor Array for Coupling with Microfluidic Delivery + = A sensor array chip with 3 rows of 8 devices is overlaid with a matching PDMS microflidic system . Indium Oxide Nanowires are grown chemically to lie across electrical ‘ source ’ and ‘ drain ’ to create a ‘ device ’. An FET array contains 3 rows of 8 devices to form a Sensor Array Chip.
  9. 9. Nanoparticle Therapeutic Delivery Vehicles <ul><li>Nanoparticles : Solid particle, can also be used in imaging </li></ul><ul><li>Nanoshells : A core of silica and a metallic outer layer. Can be injected safely . Gold surface can be functionalized, typically used for cell-kill by external activation </li></ul><ul><li>Liposomes : Lipid vesicles , can carry drugs encapsulated </li></ul><ul><li>Dendrimers : An architectural class of nanoscale chemical polymers </li></ul><ul><li>Carbon nanotubes: Can inject molecules into cells. Can be filled & capped , forming drug delivery devices </li></ul>Carbon nanotubes Dendrimer McNeil, 2005. Nanoparticle albumin-bound paclitaxel cell membrane Microvessel Lumen caveolin-1 gp60 gp60 captures circulating albumin-bound paclitaxel Caveolae: Budding and internalization of gp60 receptors with albumin-bound paclitaxel Transcytosis and intratumoral deposition of albumin-bound paclitaxel Adapted from John T.A. et al. (2003), Am. J. Physiol. Lung Cell Mol Physiol . 284, L187-L196. Tumor Interstitium Abraxane: A Novel Breast Cancer Therapeutic
  10. 10. <ul><li>Analyzing Circulating Tumor Cells (CTC) </li></ul>
  11. 11. Bone Marrow Occult Metastasis
  12. 12. <ul><li>CTC hold extraordinary potential for better management of cancer patients </li></ul><ul><ul><li>Assess potential for disease progression </li></ul></ul><ul><ul><li>Determine need for systemic therapy without invasive diagnosis </li></ul></ul><ul><ul><li>Monitor therapeutic efficacy </li></ul></ul><ul><ul><li>Testing site for cancer biomarkers </li></ul></ul><ul><ul><li>Understand early molecular events in metastasis </li></ul></ul><ul><ul><ul><li>Discover new therapeutic targets </li></ul></ul></ul>CTC : Circulating tumor cells – Tumor cells in peripheral blood Early detection of CTC in blood is difficult, because CTC are extremely rare on hematopoietic background Metastasis & Circulating Tumor Cells
  13. 13. Challenge: Detection of CTC is Very Difficult <ul><li>CTC are extremely rare events (~1/ml) </li></ul><ul><li>CTCs share many molecular traits with surrounding cells </li></ul><ul><li>Single-cell detection and analysis desirable </li></ul>
  14. 14. Mean (and range) of sizes of normal cellular components of blood, and certain cancer cell lines. Universal Platform for Cell Capture Based on Size Normal blood components Cancer cell lines 0 5 10 15 20 25 30 Platelets RBC Basophils Lymphocytes Neutrophils Eosinophils Monocytes NCI-H522 J82 RT4 HCC-70 MDA-MB-231 HT1080 T24 SK-Br-3 HCC-38 LnCaP NCI-1395 Cell size ( μ m)
  15. 15. Microfilter Based Cell Separation Assembled Filter Device Parylene Filter Membrane SEM of Cell Captured on filter Syringe 1 PDMS Chamber Parylene Membrane Filter Trapped Tumor Cell RBC’s in the flow through MNCs 100µm A B C 100µm
  16. 16. Multiplexed Imaging On-Chip Multiplex PCR Her2/neu FISH analysis on microfilter CK PSA CK PSA DAPI
  17. 17. “ Patient Management” using CTC Detection Using CTC in the blood as a “virtual” tumor biopsy Quantitation Target identification Stem cell identification Quantitation Target identification Stem cell identification Functional changes Monitoring CTC CTC CTC CTC Rx Rx Rx <ul><li>Real time therapeutic efficacy monitoring </li></ul><ul><li>Assessment of changing targets </li></ul><ul><li>Characterization of cells of interest </li></ul><ul><li>Assessment of functional change </li></ul>Diagnosis Rx
  18. 18. The Future of Medicine <ul><li>Combination of existing and novel tests based on cells, proteins and genes in one single platform </li></ul><ul><li>High sensitivity, specificity and low cost </li></ul><ul><li>Elimination of complicated laboratory procedures and equipment </li></ul><ul><li>Bedside or in-office applications (point of care) </li></ul><ul><li>Small size = increased portability </li></ul><ul><li>Deliver advanced technologies world wide </li></ul><ul><ul><li>Provide access to remote areas </li></ul></ul><ul><ul><li>Allow for new medical opportunities to underserved populations </li></ul></ul><ul><li>Widely accessible patient specific disease management </li></ul>
  19. 19. Serial CTC counts predict survival in prostate cancer Moreno et al Proc Am Soc Clin Oncol 2007;25:239s. DeBono et al, CCR , 2008, MSKCC, CCF, U Mich Kaplan–Meier plot for overall survival of CTC counts categories conversion at any time point following the early or late cycle of treatment. Survival times were calculated from the date of baseline (BL) CTC blood draw. Multivariate analysis was carried out using a Cox regression model with a time-dependant co-variable. 1 2 3 4 Curve Logrank Comparison p-Value* 1 vs. 2 0.1528 1 vs. 3 <0.0001 1 vs. 4 <0.0001 2 vs. 3 <0.0001 2 vs. 4 <0.0001 3 vs. 4 0.5013 %Probability of Survival Time from Baseline Blood Draw (Months) 0 2 4 6 8 10 12 14 16 18 22 24 26 28 30 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 20 *p-values not adjusted for multiple hypothesis tests Grp Description N (%) Median OS in months (95% CI) 1 <5 CTC at all draws 88 (38%) >26 (21.4 to -----) 2 > 5 CTC at BL & <5 CTC at last draw 45 (20%) 21.3 (18.4 to ----) 3 <5 CTC at Early Draw & > 5 CTC at Last Draw 26 (11%) 9.3 (8.2 to 11.3) 4 > 5 CTC at All Draws 71 (31%) 6.8 (5.8 to 10.3)
  20. 20. <ul><li>Single excitation source </li></ul><ul><li>Narrow emission spectrum </li></ul><ul><li>Fluorescence does not quench easily </li></ul>Quantum Dots: Inorganic Nanocrystals CdTe CdSe Emission Wavelength (nm) Excitation at 360nm 700 650 600 550 500 450 Normalized intensity 6nm 3nm 2nm 6nm
  21. 21. Nanoparticles can serve as imaging contrast agents Magnetized nanoparticles can be used to image sentinel lymph nodes Example: SentiMag technology by Endomagnetics Johnson L et al, Discov Med. 2010 Apr;9(47):374-9. QD800- based imaging agents tested in vivo are stable up to several days Yang et al, Oral Oncology, 46, 864-868, 2010
  22. 22. Cote et al J Clin Oncol. 1991 Recurrence Rates Based on Tumor Burden in the Bone Marrow
  23. 23. <ul><li>Efficient Enrichment and Capture of CTC </li></ul><ul><li>Easy post-capture molecular analysis to understand the metastasis biology </li></ul><ul><li>Simple process flow </li></ul><ul><li>Potential for point-of-care operation </li></ul><ul><li>Reliable and Reproducible Fabrication Process </li></ul>What Will an Ideal CTC Capture Platform Allow?
  24. 24. Nanosensor Platforms Team Nanosensor Collaborators Dr. Mark Thompson, USC Dr. Chong wu Zhou, USC Dr. Thomas Thundat, ORNL Dr. Ram Datar, UM Dr. Marco Curreli, USC Dr. Fumi Ishikawa, USC Dr. Henry Lin, ORNL Dr. Arun Majumdar
  25. 25. Dr. Yu Chong Tai, Caltech Dr. Ram Datar, UM Dr. Marija Balic, Austria Dr. Siyang Zheng , PennState Dr. Henry Lin, ORNL Anthony Williams, UM CTC Microfilter Team CTC Microfilter Collaborators