title: Polymeric carrier-mediated intracellular delivery of phosphatidylinositol-3,4,5-trisphosphate to overcome insulin resistance.
abstract: BACKGROUND
  Phosphatidylinositol-3,4,5-trisphosphate (PIP3) is a major lipid second messenger in insulin-mediated signalling towards the metabolic actions of this hormone in muscle and fat.
  
  
  OBJECTIVE
  Assessing the intracellular transport of exogenous PIP3 attached to a polymeric carrier in an attempt to overcome cellular insulin resistance.
  
  
  METHODS
  Artificial chromatic bio-mimetic membrane vesicles composed of dimyristoylphosphatidylcholine and polydiacetylene were applied to screen the polymeric carriers. PIP3 cellular localization and bio-activity was assessed by fluorescent and live-cell microscopy in L6 muscle cells and in 3T3-L1 adipocytes.
  
  
  CONCLUSIONS
  We demonstrate that a specific-branched polyethylenimine (PEI-25, 25 kDa) carrier forms complexes with PIP3 that interact with the bio-mimetic membrane vesicles in a manner predictive of their interaction with cells: In L6 muscle cells, PEI-25/fluorescent-PIP3 complexes are retarded at the cell perimeter. PEI-25/PIP3 complexes retain their bio-activity, engaging signalling steps downstream of PIP3, even in muscle cells rendered insulin resistant by exposure to high glucose/high insulin.
  
  
  CONCLUSIONS
  Inducing insulin actions by intracellular PIP3 delivery (PEI-25/PIP3 complexes) in some forms of insulin-resistant cells provides the first proof-of-principle for the potential therapeutic use of PIP3 in a "second-messenger agonist" approach. In addition, utilization of an artificial bio-mimetic membrane platform to screen for highly efficient PIP3 delivery predicts biological function in cells.
authors.affiliation: a Department of Chemical Engineering .
authors.forename: Ilana
authors.initials: I
authors.lastname: Kachko
authors.affiliation: a Department of Chemical Engineering .
authors.forename: Tamar
authors.initials: T
authors.lastname: Traitel
authors.affiliation: a Department of Chemical Engineering .
authors.forename: Riki
authors.initials: R
authors.lastname: Goldbart
authors.affiliation: b Department of Chemistry .
authors.forename: Liron
authors.initials: L
authors.lastname: Silbert
authors.affiliation: b Department of Chemistry .
authors.forename: Marina
authors.initials: M
authors.lastname: Katz
authors.affiliation: c Department of Clinical Biochemistry , and.
authors.forename: Nava
authors.initials: N
authors.lastname: Bashan
authors.affiliation: b Department of Chemistry .
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
authors.affiliation: c Department of Clinical Biochemistry , and.|d The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva , Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Rudich
authors.affiliation: a Department of Chemical Engineering .
authors.forename: Joseph
authors.initials: J
authors.lastname: Kost
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000008:administration & dosage* / Q000494:pharmacology; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; D011108:Polymers; C060974:phosphatidylinositol 3,4,5-triphosphate; D011094:Polyethyleneimine
keywords: Artificial bio-mimetic membrane; PI-3,4,5-P3; PIP3; diabetes type II; dimyristoylphosphatidylcholine/polydiacetylene; polyethylenimine