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Optical Bio-im aging w ith Polym er Nanoparticles I ck Chan Kw on, - PDF document

Optical Bio-im aging w ith Polym er Nanoparticles I ck Chan Kw on, Ph.D Biom edical Research Center Korea I nstitute of Sci. & Tech. 2 0 0 8 . 4 . 1 7 . US-Korea Nano Forum + Probe + Probe + Probe + Probe - I nhibitor - I


  1. Optical Bio-im aging w ith Polym er Nanoparticles I ck Chan Kw on, Ph.D Biom edical Research Center Korea I nstitute of Sci. & Tech. 2 0 0 8 . 4 . 1 7 . US-Korea Nano Forum + Probe + Probe + Probe + Probe - I nhibitor - I nhibitor + Probe + Probe + Probe + Probe OA OA Normal Normal OA OA Normal Normal Wednesday, Jan. 16, 2008 Judah Folkman, Cancer Pioneer By Alice Park M. Judah Folkman, biomedical pioneer, dies at 74 Surgeon, research scientist, teacher and mentor, created field of angiogenesis January 16, 2008 Judah Folkman, Researcher, Dies at 74 Children's m ourns the death of Dr. Judah Folkm an 1

  2. “On January 14, Dr. Judah Folkman, founder of the field of angiogenesis , died unexpectedly in Denver, Colo., while en route to Vancouver for one of the thousands of lectures that he gave to scientists around the world. A visionary and scientific pioneer, Dr. Folkman was founder and director of the Vascular Biology Program at Children's Hospital Boston, and a professor of Pediatric Surgery and Cell Biology at Harvard Medical School.” from Bess Andrews, Childrens Hospital “When Dr. Folkman first proposed, in the 1970s, that a cancer could be kept in check by cutting off its blood supply, he faced skepticism from a scientific com m unity that simply wasn't ready for his ideas. But he persevered, even when there were setbacks, and today, more than 1 ,0 0 0 laboratories w orldw ide are engaged in the study of angiogenesis, the field he founded. As a result of Dr. Folkman's vision and resilience, more than 1 0 new cancer drugs are currently on the m arket , and more than 1 .2 m illion patients w orldw ide are now receiving anti-angiogenic therapy.” from Robert Cook, Harvard Science Correspondent W hat is Tum oral Angiogenesis Pathological angiogenesis is a hallm ark of cancer. W ithout blood vessels, tum ors can not grow beyond a critical size ( ~ 5 m m in diam eter) due to the lack of oxygen and nutrients for their survival. Carm eliet et al. Nature 2 0 0 0 ;4 0 7 :2 4 9 -2 5 7 2

  3. W hen Tum oral Angiogenesis Starts Beyond the critical volum e of 2 cubic m illim eters , oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor, causing a state of cellular hypoxia that marks the onset of tum oral angiogenesis . http:/ / w w w .angiow orld.com The Angiogenesis Signaling Cascade VEGF and bFGF are first synthesized inside tumor cells and then secreted into the surrounding tissue. When they encounter endothelial cells, they bind to specific proteins, called receptors , sitting on the outer surface of the cells. The binding of either VEGF or bFGF to its appropriate receptor activates a series of relay proteins that transmits a signal into the nucleus of the endothelial cells. The nuclear signal ultimately prompts a group of genes to m ake products needed for new endothelial cell grow th. 3

  4. Endothelial Cell Activation The activation of endothelial cells by VEGF or bFGF sets in motion a series of steps toward the creation of new blood vessels. First, the activated endothelial cells produce matrix m etalloproteinases (MMPs) . The MMPs break down the extracellular matrix — support material that fills the spaces between cells and is made of proteins and polysaccharides. Breakdown of this matrix permits the migration of endothelial cells. As they migrate into the surrounding tissues, activated endothelial cells begin to divide. The Angiogenic Sequence • A cell activated by a lack of oxygen releases angiogenic molecules that attract inflam m atory and endothelial cells and promote their proliferation. • During their migration, inflammatory cells also secrete molecules that intensify the angiogenic stimuli. • The endothelial cells that form the blood vessels respond to the angiogenic call by differentiating and by secreting matrix m etalloproteases (MMP), which digest the blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli. http:/ / w w w .angiow orld.com 4

  5. Perm eablility of Angiogenic Vessel Hobbs SK et. al. Proc Natl Acad Sci USA 1 9 9 8 ;9 5 :4 6 0 7 - 4 6 1 2 . 5

  6. EPR effect ( Enhanced Perm eability And Retention) Accumulation of Evans blue-albumin complex in tumor tissue and normal skin in tumor-bearing mice. Tumor S-180 was injected into the skin. NI F channel 0h 0h 6 h 6 h 12 h 12 h 1day 1day 2day 2day 3day 3day 5 day 5 day 6day 6day 1 0 μ g/ m l 5 0 μ g/ m l NI F + W hite light channel 0h 0h 6h 6h 12h 12h 1day 1day 2day 2day 3day 3day 1 0 0 μ g/ m l 1 m g/ m l 4 day 5 day 3 day Cy 5 .5 GC-Cy 5 .5 HGC-Cy 5 .5 Norm al 6

  7. I m aging Angiogenesis Activatable Nanoparticle Gold Nanoparticle for MMP Activation AuNP Cy5.5 AuNP Probe Sub. Cy5.5 Sub. Absorbance (a.u.) AuNP Probe - DTT AuNP + DTT 400 500 600 700 800 Wavenumber (nm) I n press, Angew Chem I ntern Ed ( 2 0 0 8 ) 7

  8. Gold Nanoparticle for MMP Activation Fluorescence Intensity (a.u.) Fluorescence Intensity (a.u.) 1200 1200 w/o MMP w/ MMP-2 (M2) 1000 1000 w/ MMP-3 (M3) w/ MMP-7 (M7) 800 800 w/ MMP-13 (M13) w/ MMP-2/Scramble (M2S) 600 600 w/ MMP-2/Inhibitor (M2I) 400 400 200 200 0 0 700 720 740 760 780 800 0 20 40 60 80 100 120 Wavenumber (nm) Time (min) Buffer M2 M3 M7 M13 M2S M2I 0 1 3 7 14 MMP-2 conc. (nmol/L) I n press, Angew Chem I ntern Ed ( 2 0 0 8 ) Gold NP for MMP-2 positive Tum or I m aging I n press, Angew Chem I ntern Ed ( 2 0 0 8 ) 8

  9. Long Circulating Self-assem bled Glycol Chitosan Nanoparticle 6H 12H 1day 2day 3day 4day 5day 1H 6day 7day 8day 9day 10day • SCC-7cell (3x106 cell), tail vein injection of HGC-Cy5.5 (5mg/ kg) Self-assem bled Glycol Chitosan Nanoparticle CH 2 OCH 2 CH 2 OH CH 2 OCH 2 CH 2 OH O O PBS (pH 7.4) O O HO HO NH 2 NH S n m r o f o r o l h C n o i t a c i n o S ` 5 0 0 nm 3 3 3 nm 1 5 0 nm Decrease in polymer concentraion Published in Colloid Polym Sci ( 2 0 0 6 ) 2 8 4 : 5 0 6 – 5 1 2 9

  10. Polym er NP for MMP-2 positive Tum or I m aging 1 2 3 1: MMP-2 probe 2: MMP-2 probe + inh. 3: No treat Probe Probe + inh. No treat MMP-2 Molecular I m aging Visualization of biological process Molecular events at m olecular and celluar level I n living system s Using rem ote im aging detectors “The characterization and m easurem ent of biological processes in living anim als, m odel system s, and hum ans at the cellular and m olecular level by using rem ote im aging detectors” Lucker GD and Piw nica-W orm s D Acad. Radiol. 2 0 0 1 ;8 ;4 10

  11. Reduction in Tum or Size MMP-1 3 Specific Nanoprobe for OA 11

  12. Histology vs. MMP-13 Detection Histology vs. MMP-13 Detection Histology Grading MMP-13 Expression Normal: Left Grade 4 OA: Right Grade 3 Grade 2 Grade 1 Normal 2 4 6 8 10 12 weeks Theragnosis Diagnosis, Molecular I m aging Targeted Therapy Evaluation of Therapeutic Effect 12

  13. Future of Medicine Theranostic Personalized Biom arkers im aging Medicine DNA Lazer Optics Protein Photosensitizer Photonics DNA probes Protein probes RNA Abnorm al cell RNA probes Metabolite probes Molecular Metabolite Probes Bioinform atics Tailored Pharm aceuticals 13

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