We previously reported that siRNA delivery to the brain is improved by the nose-to-brain\ndelivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer\nmicelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the\nnose-to-brain delivery of siRNA targeting TNF-Alpha (siTNF-Alpha) conjugated with PEG-PCL-Tat to\ninvestigate its therapeutic effects on a transient middle cerebral artery occlusion (t-MCAO) rat\nmodel of cerebral ischemia-reperfusion injury. Intranasal treatment was provided 30 min after\ninfarction induced via suturing. Two hours after infarction induction, the suture was removed,\nand blood flow was released. At 22 h post-reperfusion, we assessed the infarcted area, TNF-Alpha\nproduction, and neurological score to determine the therapeutic effects. The infarcted area was\nobserved over a wide range in the untreated group, whereas shrinkage of the infarcted area was\nobserved in rats subjected to intranasal administration of siTNF-Alpha with PEG-PCL-Tat micelles.\nMoreover, TNF-Alpha production and neurological score in rats treated by intranasal administration of\nsiTNF-Alpha with PEG-PCL-Tat micelles were significantly lower than those in untreated and naked\nsiTNF-Alpha-treated rats. These results indicate that nose-to-brain delivery of siTNF-Alpha conjugated with\nPEG-PCL-Tat micelles alleviated the symptoms of cerebral ischemia-reperfusion injury.
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