RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

David L. Gillespie, Maria T. Aguirre, Sandhya Ravichandran, Lisa L. Leishman, Claudia Berrondo, Joseph T. Gamboa, Libo Wang, Rose King, Xuli Wang, Mingqian Tan, Anthony Malamas, Zheng Rong Lu, Randy L. Jensen

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

OBJECT: High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1α (HIF-1α) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. METHODS: Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1α in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(aminoethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convection-enhanced delivery. RESULTS: Mice receiving daily siRNA injections targeting HIF-1α had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CONCLUSIONS: Treating glioblastoma with siRNA targeting HIF-1α in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.

Original languageEnglish (US)
Pages (from-to)331-341
Number of pages11
JournalJournal of neurosurgery
Volume122
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • Glioma
  • HIF-1α
  • Intracranial
  • Knockdown
  • Mouse
  • Oncology
  • RNA interference
  • Tumor
  • siRNA

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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  • Cite this

    Gillespie, D. L., Aguirre, M. T., Ravichandran, S., Leishman, L. L., Berrondo, C., Gamboa, J. T., Wang, L., King, R., Wang, X., Tan, M., Malamas, A., Lu, Z. R., & Jensen, R. L. (2015). RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model. Journal of neurosurgery, 122(2), 331-341. https://doi.org/10.3171/2014.10.JNS132363