Intranasal delivery of hGDNF plasmid DNA nanoparticles results in long-term and widespread transfection of perivascular cells in rat brain

The intranasal route of administration allows large therapeutics to circumvent the blood–brain barrier and be delivered directly to the CNS. Here we examined the distribution and pattern of cellular transfection, and the time course of transgene expression, in the rat brain after intranasal delivery...

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Veröffentlicht in:Nanomedicine 2019-02, Vol.16, p.20-33
Hauptverfasser: Aly, Amirah E-E., Harmon, Brendan, Padegimas, Linas, Sesenoglu-Laird, Ozge, Cooper, Mark J., Yurek, David M., Waszczak, Barbara L.
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Sprache:eng
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Zusammenfassung:The intranasal route of administration allows large therapeutics to circumvent the blood–brain barrier and be delivered directly to the CNS. Here we examined the distribution and pattern of cellular transfection, and the time course of transgene expression, in the rat brain after intranasal delivery of plasmid DNA nanoparticles (NPs) encoding hGDNF fused with eGFP. Intranasal administration of these NPs resulted in transfection and transgene expression throughout the rat brain, as indicated by eGFP ELISA and eGFP-positive cell counts. Most of the transfected cells were abluminal and immediately adjacent to capillaries and are likely pericytes, consistent with their distribution by perivascular transport. Intranasal administration of these plasmid DNA NPs resulted in significant, long-term transgene expression in rat brain, with highest levels at 1 week and continued expression for 6 months. These results provide evidence in support of intranasal DNA NPs as a non-invasive, long-term gene therapy approach for various CNS disorders. Intranasal administration of plasmid DNA nanoparticles expressing hGDNF (pUGG NPs) results in transfection of perivascular cells in the brain. (1) Intranasally delivered pUGG NPs are distributed along the rostral–caudal axis of the brain in the perivascular spaces surrounding capillary endothelial cells (EC). (2) pUGG NPs transfect primarily perivascular cells that are located abluminal and immediately adjacent to capillaries. (3) These transfected perivascular cells, which are likely pericytes, express the transgene, i.e. the reporter protein eGFP. AC: astrocyte; EC: endothelial cell; eGFP: enhanced green fluorescent protein; M: microglia; N: neuron; PC: pericyte or perivascular macrophage; PVS: perivascular space. [Display omitted]
ISSN:1549-9634
1549-9642
DOI:10.1016/j.nano.2018.11.006