title: RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model.
abstract: OBJECTIVE
  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.
authors.affiliation: Huntsman Cancer Institute and Department of Neurosurgery and.
authors.forename: David L
authors.initials: DL
authors.lastname: Gillespie
authors.forename: Maria T
authors.initials: MT
authors.lastname: Aguirre
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ravichandran
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Leishman
authors.forename: Claudia
authors.initials: C
authors.lastname: Berrondo
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Gamboa
authors.forename: Libo
authors.initials: L
authors.lastname: Wang
authors.forename: Rose
authors.initials: R
authors.lastname: King
authors.forename: Xuli
authors.initials: X
authors.lastname: Wang
authors.forename: Mingqian
authors.initials: M
authors.lastname: Tan
authors.forename: Anthony
authors.initials: A
authors.lastname: Malamas
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004151:Dipeptides; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; C541916:N-(1-aminoethyl)iminobis(N-(oleoyl-cysteinyl-histidyl-1-aminoethyl)propionamide); D034741:RNA, Small Interfering; C495678:Slc2a1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse
keywords: CA-IX = carbonic anhydrase-IX; CED = convection-enhanced delivery; DAB = 3,3′-diaminobenzidine tetrahydrochloride; DCA = dichloroacetate; EHCO = 1-(aminoethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide]; GFP = green fluorescent protein; GLUT-1 = glucose transporter 1; HIF-1α; HIF-1α = hypoxia-inducible factor 1α; IHC = immunohistochemistry; MVD = microvascular density; PEG = polyethylene glycol; PI = proliferation index; RNA interference; RNAi = RNA interference; VEGF = vascular endothelial growth factor; glioma; intracranial; knockdown; mouse; oncology; siRNA; siRNA = small interfering RNA; tumor