Hsp90-targeted miRNA-liposomal formulation for systemic antitumor effect

Biomaterials. 2013 Sep;34(28):6804-17. doi: 10.1016/j.biomaterials.2013.05.054. Epub 2013 Jun 14.


Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small molecule-based regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • COS Cells
  • Cell Line, Tumor
  • Female
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Liposomes / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / genetics*
  • NIH 3T3 Cells
  • Polymerase Chain Reaction
  • Receptors, Glucocorticoid / metabolism


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Liposomes
  • MicroRNAs
  • Receptors, Glucocorticoid