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Module 1-b Angiogenesis

Module 1-b Angiogenesis. Angiogenesis. In order for a tumor to grow beyond 2 mm^3, it must have a steady supply of amino acids, nucleic acids, carbohydrates, oxygen, and growth factors for metastasis and continued growth.

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Module 1-b Angiogenesis

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  1. Module 1-bAngiogenesis

  2. Angiogenesis In order for a tumor to grow beyond 2 mm^3, it must have a steady supply of amino acids, nucleic acids, carbohydrates, oxygen, and growth factors for metastasis and continued growth. Tumors must stimulate angiogenesis, the growth of new blood vessels from preexisting ones so as to obtain these nutrients.

  3. Cascade of Events in Angiogenesis The endothelial cell's machinery begins to produce new molecules including enzymes. These enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels. Newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins. The endothelial cells begin to divide (proliferate) and migrate out through the dissolved holes of the existing vessel towards the diseased tissue (tumor). Matrix metalloproteinases (MMP) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it.  Specialized molecules called adhesion molecules called integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward. Sprouting endothelial cells roll up to form a blood vessel tube. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood. The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus.

  4. Angiogenic Switch Angiogenic Switch Balance is important in every aspect of life !

  5. Antiangiogenesis Targets for Therapy and Imaging Neovasculature Proteases that breakdown the ECM (e.g. MMPs) Growth factors that stimulate endothelial cell proliferation (e.g. VEGF, PDGF, bFGF, IL-8) Integrins that allow adhesion of endothelial cells (e.g. avb3) Endothelial cell apoptosis (e.g. TNF…) Pre-existing Vasculature Various Vasculature Targeting Agents

  6. Timeline of Anti-angiogenic Therapy 1971: The field began in early 1970s with Judah Folkman’s hypothesis that tumor growth would be halted if it were deprived of a blood supply 1989: Dr. NapoleneFerra identified and isolate VEGF 1996: Dr. Jeffery Isner published first clinical trials regarding VEGF 2004: FDA approves first antiangiogenic drug to treat colorectal cancer (Avastin)

  7. Is it possible to detect neo-angiogenic vessels ? Au The specificity of αvβ3-integrin –NP was demonstrated by inhibiting αvβ3 -transfected K293 cell binding to vitronectin. Effective affinity = 50 pM (per particle). 300 copies/Nanoparticle 80-150nm Integrin avb3-Targeted Gold NanoBeacons (GNB) Early angiogenic vessels Sprouting No full circulation yet Pan et al. 2010 FASEB J, 25, 875-882

  8. Nanobeacons for Photoacoustic Imaging avb3-Targeted gold nanobeacons TEM Inner matrix: Veg oil / polysorbate “Self-assembly” Phospholipids (1) Probe sonication; (2) Homogenization (20,000 psi, 4°C, 4 min) Kd < 10 nM 80-150nm Au AFM A “particle within particle” approach Pan et. al. 2010 FASEB J, 25, 875-882 Pan et. al. ACS Nano. 2012 Feb 28;6(2):1260-7.  Pan et. al. Angew Chem Int Ed 48,4170 (2009) Pan et al. Nanosci and Nanotech 2010, 10(12):8118-23.

  9. How Early We Are Able to Detect? Early detection of immature, nascent angiogenic vessels with Photoacoustics Imaging! MATRIGEL MOUSE MODEL 720 nm 720 nm 720 nm 14 days avb3-GNB Red arrows denote small neovascular sprouts arising from immature angiogenic vessels with only nascent blood flow. Pan et al. 2010 FASEB J, 25, 875-882

  10. Atherosclerotic Plaque and Angiogenesis Seeing and quantifying atherosclerotic angiogenesis in cholesterol-fed rabbit with avb3-Mn nanocolloids In vivo T1 sagittal section spin-echo image to display long axis of aorta from aortic arch to diaphragm of cholesterol-fed rabbit • Linking of angiogenesis with atherosclerotic plaque • A possible marker for vulnerable plaque • Sensitivity of detection • Target specificity Pan D. et al. Circulation 2010, 122, A20216

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