Block-copolymer micelles as carriers of cell signaling modulators for the inhibition of JNK in human islets of Langerhans

Biomaterials. 2009 Jul;30(21):3597-604. doi: 10.1016/j.biomaterials.2009.03.028. Epub 2009 Apr 1.

Abstract

Here we investigate the potential of PCL-b-PEO micelles in preventing the cell death of isolated human islets of Langerhans. PCL-b-PEO micelles were loaded with c-Jun NH2-terminal kinases inhibitor SP600125 to rescue the isolated islets. Mechanistic studies of the uptake were conducted in PC12 cells. Incorporation of SP600125 afforded 8.2 fold greater solubility of SP600125 in micelle suspension. To investigate the effectiveness of micelle-incorporated SP600125 in preventing the islet cell death, we challenged the islets with TNF-alpha, IL-1, and IFN gamma. Micelle-incorporated SP600125 did not lose its inhibitory activity during incorporation into micelles, and it protected the islets against cytokine-induced loss of viability to the same extent as control SP600125. Moreover, the concentration of micelle-incorporated SP600125 used was 13-fold lower, demonstrating the greater efficacy of micelle delivered SP600125. Micelles maintained their cytoplasmic distribution without detectable nuclear localization in islets. The inhibition of JNK was confirmed by western blots. This study suggests that micelle-based intracellular delivery of potent, poorly water soluble, cell-death-pathway inhibitors may represent a valuable addition to established delivery of cytocidal block-copolymer micelle-incorporated bioactives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / chemistry
  • Anthracenes / pharmacokinetics
  • Anthracenes / pharmacology
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Drug Carriers / chemistry*
  • Drug Carriers / pharmacokinetics
  • Humans
  • In Vitro Techniques
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / metabolism*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Micelles
  • PC12 Cells
  • Polymers / chemistry*
  • Polymers / pharmacokinetics
  • Rats

Substances

  • Anthracenes
  • Drug Carriers
  • Micelles
  • Polymers
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases