284023 Active Stealth Signaling with a Synthetic 'self' Peptide

Wednesday, October 31, 2012: 12:30 PM
Somerset West (Westin )
Dennis E. Discher, Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA

Foreign particles and cells are rapidly cleared from the body by professional phagocytes that incessantly encounter and recognize ‘self’ cells.  The membrane protein CD47 is reportedly a ‘Marker of Self’ in mouse that impedes phagocytosis of self cells, with signaling through the highly polymorphic receptor CD172a on phagocytes.  Here, minimal ‘Self’ peptides were computationally designed from CD47human, synthesized with anchoring groups, and attached to virus-size nanoparticles for intravenous injection into NOD.SCID (NSG) mice that express a unique CD172aNSG (SIRPA) compatible with CD47human.  ‘Self’ peptides delay splenic macrophage clearance of particles with an exponential advantage in persistent circulation, which we use to enhance near-infrared imaging of human tumor xenografts by >10-fold.  The affinity of CD47human for CD172aNSG proves weak but within the broad range (0.1 ~ 5 micro-Molar) measured for ten constructed variants of CD172ahuman; several versions of ‘Self’ peptide are likewise shown to bind and potently inhibit nanoparticle uptake by an unexpected cytoskeletal mechanism.  The reductionist approach reveals the importance and utility as well as some limits of a human ‘Self’ peptide.

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