Polymeric carrier-mediated intracellular delivery of phosphatidylinositol-3,4,5-trisphosphate to overcome insulin resistance

Ilana Kachko, Tamar Traitel, Riki Goldbart, Liron Silbert, Marina Katz, Nava Bashan, Raz Jelinek, Assaf Rudich, Joseph Kost

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.Purpose: 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.Results and discussion: 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.

Original languageEnglish
Pages (from-to)698-709
Number of pages12
JournalJournal of Drug Targeting
Issue number7-8
StatePublished - 14 Sep 2015


  • Artificial bio-mimetic membrane
  • PI-3-P
  • PIP
  • diabetes type II
  • dimyristoylphosphatidylcholine/polydiacetylene
  • polyethylenimine

ASJC Scopus subject areas

  • Pharmaceutical Science


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