P atients with the most malignant type of glioma, Grade IV glioblastoma, have a mean survival time of approximately 15 months and an estimated 5-year survival rate of less than 5%.11 High-grade gliomas (Grades III and IV) are the most common primary brain tumors in adults and the fourth leading cause of cancerrelated death. 40 Tumor hypoxia is thought to play an important role in glioblastoma tumor pathobiology by proabbreviatioNs 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-1a = hypoxia-inducible factor 1a; IHC = immunohistochemistry; MVD = microvascular density; PEG = polyethylene glycol; PI = proliferation index; RNAi = RNA interference; siRNA = small interfering RNA; VEGF = vascular endothelial growth factor. 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 1a (HIF-1a) 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-1a in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(amino ethyl)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, convectionenhanced delivery. resUlts Mice receiving daily siRNA injections targeting HIF-1a 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-1a in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.
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