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

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.

Use of loteprednol for routine prophylaxis after photorefractive keratectomy.

BACKGROUND: The purpose of this work is to report our experience using loteprednol 0.5% for routine prophylaxis after photorefractive keratectomy in an academic refractive surgery center. MATERIALS AND METHODS: Photorefractive keratectomy was performed on 579 eyes from 316 patients in this retrospective chart review of patients treated postoperatively with either fluorometholone 0.1% (273 eyes) or loteprednol 0.5% (306 eyes). Primary outcome measures at 6 months included uncorrected distance visual acuity, corrected distance visual acuity, and manifest refraction spherical equivalent. Secondary outcome measures were incidence of corneal haze and increased intraocular pressure. RESULTS: There were no statistically significant differences in preoperative characteristics between the two groups when comparing age, sex, best-corrected visual acuity, spherical equivalent, or keratometry. Both groups achieved excellent visual outcomes, with a mean uncorrected distance visual acuity (logMAR) of 0.004 ± 1.4 in the fluorometholone group and -0.028 ± 1.1 in the loteprednol group (P = 0.013) at 6 months. Postoperative corneal haze and increased intraocular pressure were uncommon and not statistically different between the groups. CONCLUSION: Loteprednol 0.5% performed similarly to fluorometholone 0.1% when used for prophylaxis following photorefractive keratectomy. The incidence of haze and increased intraocular pressure were similar between the two groups.