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A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System
Published on: August 15, 2019
Intranasal Tat-modified PEG-PCL nanomicelles delivering anti-RelA siRNA attenuate ischemia-reperfusion injury
Mitsuyoshi Fukuda1, Takayuki Oguma2, Taiki Nagatomo1
1Laboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Abstract:
Inflammatory responses centered on microglial activation are deeply involved in the progression of cerebral ischemia-reperfusion injury, and RelA, a subunit of nuclear factor κB (NF-κB), acts as a central mediator of these responses. In this study, we evaluated the efficacy of a nose-to-brain drug delivery system that combines intranasal administration with polymeric nanomicelles modified with the cell-penetrating peptide Tat (polyethylene glycol [PEG]-polycaprolactone [PCL]-Tat) to deliver RelA-targeting small interfering RNA (siRNA), referred to as siRelA. The PEG-PCL-Tat-siRelA complex exhibited efficient intracellular uptake by BV-2 microglial cells and significantly suppressed RelA mRNA expression. No significant cytotoxicity was observed in BV-2 or primary cultured mouse hippocampal neurons. In addition, the complex showed high siRNA stability in the cerebrospinal fluid. Using a radiolabeled model siRNA, intranasal administration of PEG-PCL-Tat to mice subjected to transient middle cerebral artery occlusion (t-MCAO) significantly enhanced siRNA distribution in ischemic brain regions. Intranasal administration of PEG-PCL-Tat-siRelA significantly reduced the infarct volume in ischemic brain regions of the t-MCAO model mice. Furthermore, suppression of RelA mRNA expression in ischemic brain tissue was accompanied by significant reductions in the mRNA expression of NF-κB-downstream inflammatory cytokines. Taken together, these results suggest that intranasal delivery of siRelA using PEG-PCL-Tat represents a promising novel neuroprotective therapeutic strategy mediated by the modulation of inflammatory responses.
Insights
This study shows that intranasal delivery of RelA-targeting siRNA using PEG-PCL-Tat nanomicelles effectively reduces brain damage after ischemic stroke. This novel neuroprotective strategy modulates inflammatory responses for potential therapeutic use.
Area of Science:
- Neuroscience
- Pharmacology
- Biotechnology
Background:
- Microglial activation and nuclear factor κB (NF-κB) signaling, mediated by RelA, are crucial in cerebral ischemia-reperfusion injury.
- Effective drug delivery to the brain remains a significant challenge for treating neurological disorders.
Purpose of the Study:
- To evaluate a novel nose-to-brain delivery system for RelA-targeting small interfering RNA (siRNA) to treat cerebral ischemia-reperfusion injury.
- To assess the efficacy and safety of intranasal administration of PEG-PCL-Tat-siRelA.
Main Methods:
- Development of polyethylene glycol (PEG)-polycaprolactone (PCL)-Tat modified nanomicelles for siRNA delivery.
- In vitro assessment of intracellular uptake, RelA mRNA suppression, and cytotoxicity in microglial and neuronal cells.
- In vivo evaluation of siRNA distribution, infarct volume reduction, and inflammatory marker expression in a mouse model of transient middle cerebral artery occlusion (t-MCAO).
Main Results:
- PEG-PCL-Tat-siRelA demonstrated efficient uptake by microglial cells and suppressed RelA mRNA expression without significant cytotoxicity.
- The nanomicelle complex showed high siRNA stability in cerebrospinal fluid.
- Intranasal administration enhanced siRNA distribution in ischemic brain regions and significantly reduced infarct volume and downstream inflammatory cytokine expression in the t-MCAO model.
Conclusions:
- Intranasal delivery of siRelA using PEG-PCL-Tat nanomicelles is a promising neuroprotective strategy for cerebral ischemia-reperfusion injury.
- This approach effectively modulates inflammatory responses by targeting the NF-κB pathway.
- The study highlights the potential of targeted nanomicelle delivery for treating ischemic stroke.
